永倉 透記

OBJECTIVES: Chronic pain is defined as pain that persists or recurs for more than 3 months. This study focuses on neuropathic pain (NP) and fibromyalgia (FM) which are chronic pain states, and aims to identify lifestyle habits associated with their prevalence. Other neurological disorders are also analyzed as references. METHODS: Association between the variable referring to disease prevalence (number of claims for reimbursement of marker drugs) and the variable for lifestyle habits/health examination results (collected from insured individuals aged 40-74 years) was determined by analyzing Japanese nationwide datasets, which were collected in 2018 and aggregated by prefecture. Pregabalin, donepezil, and levodopa were used as marker drugs for the chronic pain states, dementia-related diseases (Alzheimer's disease and Lewy body dementia) and Parkinson's disease (PD), respectively. Pearson's correlation analysis and multiple linear regression analysis were conducted. RESULTS: Variables showing correlation coefficient (|r|)>0.5 were put into the multiple linear regression. Exercise habits (ꞵ=-0.3182), smoking habits (0.3218), daily drinking (0.2683), and alanine aminotransferase>51 U/L (0.2309) were finally incorporated in the equation for pregabalin (R 2=0.7268). Walking speed (-0.4543) and daily drinking (0.5077) were incorporated in the equation for donepezil (R 2=0.5718). CONCLUSIONS: The prevalence of chronic pain states is associated with lifestyle habits, just like the dementia-related diseases. Exercise in daily life is negatively associated with the prevalence of the chronic pain states, although excessive alcohol drinking, smoking, and high serum ALT are positively associated with it. The prevalence of PD seems less associated with lifestyle habits.

INTRODUCTION: Fibromyalgia (FM) is a chronic pain condition characterized by widespread pain and complex comorbidities with a high unmet medical need. Given few past successes in the launch of analgesics with new mechanisms, the implementation of practical biomarkers for drug discovery and development would be necessary to rationally create innovative drugs for chronic pain conditions, including FM. AREAS COVERED: This review surveys the evidence on pathophysiology of FM and the findings regarding the pathophysiology-associated practical biomarker candidates in body fluids (e.g. blood) from the studies in FM patients. This review also summarizes the most commonly used animal models simulating key aspects of clinical FM features. Finally, a strategy for rationally creating innovative drugs for FM is discussed. EXPERT OPINION: Drug discovery and development for FM targeting immune dysregulation/inflammation would be a viable strategy based on the availability of the pathophysiology-associated practical biomarkers (e.g. serum interleukins), which monitor the efficacy of interventions and/or identify responders based on the matching pathophysiology throughout the process from animal models to patients. This strategy could lead to a breakthrough in the development of drugs for FM, a chronic pain condition.

OBJECTIVES: Benign prostatic hyperplasia (BPH) refers to nonmalignant hyperplasia of prostate tissue, which causes lower urinary tract symptoms and has become a global public health concern in the aging population. The purpose of this study is to identify modifiable factors, which would prevent or delay BPH development. METHODS: The association between BPH marker drugs and climate-, socioeconomic-, health condition-, and lifestyle habits-related variables was investigated by analyzing nationwide datasets which were collected in 2018, aggregated by prefecture (administrative unit), and published by Japanese ministries. Uroselective α1 receptor blockers and dutasteride were used as marker drugs referring to BPH prevalence. Correlation analysis, multiple linear regression analysis, and binomial logistic regression analysis were conducted with 47 Japanese prefectures as the unit. RESULTS: The variables which showed |r| > 0.5 by correlation analysis were exercise habits (r = -0.5696), smoking habits (r = 0.6116), and daily drinking (r = 0.6001) for uroselective α1 receptor blockers, and antihypertensive medication (r = 0.5971), smoking habits (r = 0.6598), a small amount of drinking (r = -0.5292), and serum alanine aminotransferase (r = 0.6814) for dutasteride. Multiple linear regression equations were constructed by including these variables (R 2  = 0.5453 for uroselective α1 receptor blockers and R 2  = 0.5673 for dutasteride). Binomial logistic regression analysis found a significant association between climate in the resident area and BPH development. CONCLUSION: This ecological study, analyzing Japanese nationwide datasets, demonstrates that healthy lifestyle habits, especially avoidance of smoking, implementation of exercise in daily life, and a small amount of alcohol consumption, are important to prevent or delay BPH development. High blood pressure and high serum alanine aminotransferase are suggested as risk factors of BPH development.

Nociplastic pain, the third category of chronic pain, has emerged as a serious medical issue. Due to its significant negative influences on patients and society, high prevalence, and lack of sufficiently effective treatments, more efficacious therapies are required. This review highlights the potential therapeutic approaches identified in studies that used reserpine-induced myalgia (RIM) animal model that exhibits nociplastic pain-associated phenotypes. These studies have revealed that biological processes including the chronic reduction of monoamines, increase of oxidative/nitrosative stresses and inflammatory mediators, upregulation of pronociceptive neurotransmitters and their receptors, increase of trophic factors, enhancement of the apoptotic pathway, sensory nerve sensitization, and activation of immune cells in central and/or peripheral regions, underly the nociplastic pain-associated phenotypes in RIM animal model. Potential therapeutic approaches to nociplastic pain, i.e., 1) functional modification of specific molecules which expression is distinctly altered following monoamine reduction, 2) targeting the molecules which are responsible for other major categories of chronic pain (i.e., chronic inflammatory pain and neuropathic pain), 3) supplementation of nutrition to correct the disrupted nutritional balance, 4) improvement of physical constitution by natural substances, and 5) nonpharmacological interventions, have been identified. Significance Statement Studies in RIM animal model have revealed the pathologies that occur after the chronic reduction of monoamines and identified potential therapeutic approaches to nociplastic pain. Translation of their analgesic efficacy from RIM animal model to patients remains an issue to be addressed. Successful translation would lead to better therapies for nociplastic pain.

This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.

In Japan, population health with life expectancy (LE) and healthy life expectancy (HALE) as indicators varies across the 47 prefectures (administrative regions). This study investigates how health examination results, including attitude toward improving life habits, are associated with population health. The association between health checkup variables and summary population health outcomes (i.e., life expectancy and healthy life expectancy) was investigated using a cross-sectional ecological design with prefectures as the unit of analysis. The medical records, aggregated by prefecture, gender, and age in the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan, were used as health checkup variables. Body weight, blood pressure, liver enzymes, drinking habits, smoking habits, diabetes, serum lipids, and answers to questions regarding attitude toward improving health habits were significantly correlated to population health outcomes. Multiple regression analysis also revealed significant influence of these variables on population health. This study highlights that health examination results, including attitude toward improving health habits, are positively associated with population health. Consequently, implementing measures to improve health habits in response to the examination results could help the population maintain a healthy life.

This study investigated differences in the color association with energy drinks between two populations in different cultures, i.e., Taiwanese and Japanese. An anonymous, self-administered paper questionnaire was administered to first- and second-year students at National Taiwan Normal University (Taiwan) and Naragakuen University (Japan). In our inter-country, gender-stratified comparison, the color selected most often in response to the question, “What color comes to your mind for energy drink label?” was red for the Taiwanese and blue for the Japanese. The color associations with energy drinks selected by 20% or more participants in at least one population and showing statistical difference were extracted as noticeable difference. The present study demonstrates that the color and energy drink functions are closely associated. Specifically, yellow and nourishment, black and stimulant, yellow and vitamin supplement, green and dietary fiber supplement, and red and iron supplement are tightly associated regardless of the country. The strong tie between cosmetic and white is specific to the Taiwanese consumers. This suggests that careful color selection based on consumers’ environmental and cultural backgrounds is important in communicating information regarding energy drink functions. It would be worth for energy drink manufacturers to consider those associations in designing labels for products.

The method shown in this article simulates spontaneous pain in patients with nociplastic pain using rats; the measurement with this method could be related to better translation of analgesic efficacies of therapeutic compounds between rats and humans. Nociplastic pain occurs in various disorders including fibromyalgia. Because the pain in patients occurs without an external stimulus, we assessed spontaneous pain in rats. The grimace scale, a methodology for rating facial expression, has been used for measuring spontaneous pain in animals. However, the responses in animals have been rather short-lived, and the scale has never been applied to animals exhibiting nociplastic pain. Here, we apply the rat grimace scale (RGS) to the reserpine-induced fibromyalgia-like rat, which induces nociplastic pain. The ratings of the orbital tightening, nose/cheek flattening, and changes in characteristics of ears and whiskers by three raters, who were blinded to the treatment allocated to rats, demonstrated substantial, long-lasting change in facial expression of rats. In this article, reference images for raters, and sample images used for rater training are provided. All raters independently indicated that the RGS score is significantly elevated with this methodology in reserpine-induced fibromyalgia-like rats.•The grimace scale, a method for rating facial expression, is applied to the reserpine-induced fibromyalgia-like rat, which manifests nociplastic pain.•Facial expression change in the reserpine-induced fibromyalgia-like rat is substantial and long-lasting.•Elevation of the RGS score in the reserpine-induced fibromyalgia-like rat may simulate spontaneous pain in patients with nociplastic pain.

Introduction: Chronic pain is a major healthcare issue owing to its high prevalence, significant physical and emotional burden on the patients, and huge financial burden on the society. The efficacy of currently available medications is unsatisfactory owing to their limited effect size and the low responder rate (less than 50%). Thus, there is a large unmet need for innovative therapies for chronic pain. Areas covered: In this review, the author points out the need for fundamental reforms in pain research. For the last several decades, drug discovery research has extensively focused on designing new therapies using animal models of chronic pain. It has, however, made insufficient progress with respect to the launch of innovative analgesic drugs, because the translation from preclinical to clinical stages has not been satisfactory. Thus, the strategies for developing innovative analgesic drugs are discussed. Expert opinion: Points to be considered in the discovery of drugs for pain relief include: (1) the exclusion of bias incorporation and the alignment of clinical and preclinical endpoints in the assessment of analgesic efficacy; (2) the understanding of primary unmet needs; (3) the assessment of new therapies by biomarker-prioritized frameworks, and (4) the stratification of chronic pain sufferers.

Given that patients with neuropathic pain suffer a mixture of spontaneous and evoked pain symptoms, we assessed the effects of drugs with different mechanism of action on spontaneous and evoked pain-associated behaviors in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Frequent aberrant limb movement on the operated side was measured to assess spontaneous pain-associated behavior, and mechanical allodynia and thermal hyperalgesia were evaluated to assess evoked pain-associated behaviors. These three types of behavior were assessed after administration of the following drugs: pregabalin (alpha 2 delta-subunit ligand), morphine (mu-opioid receptor agonist), perampanel (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist), clonidine, dexmedetomidine (alpha 2-adrenoceptor agonists), and diclofenac (non-steroidal anti-inflammatory drug [NSAID]). Pregabalin at an oral dose of 10 or 30 mg/kg significantly alleviated frequent aberrant limb movement and mechanical allodynia, but not thermal. hyperalgesia. Morphine at a subcutaneous dose of 1 or 3 mg/kg significantly improved all three types of behavior. Perampanel at an oral dose of 1 mg/kg attenuated only frequent aberrant limb movement. Intraperitoneal administration of clonidine (0.01 or 0.03 mg/kg) and dexmedetomidine (0.03 mg/kg) significantly improved all three types of behavior, while diclofenac did not relieve any of the behaviors. Pregabalin, clonidine, and dexmedetomidine significantly decreased motor performance at doses close to analgesic doses in the rotarod test. The present study demonstrates that responses to spontaneous and evoked pain symptoms in neuropathic pain condition differ depending on a drug's mechanism of action. The selection and application of drugs according to the specific symptoms would be considered for the medication of patients with neuropathic pain. (C) 2015 Elsevier Inc. All rights reserved.

Objective: Osteoarthritis (OA) patients experience exaggerated pain during movements such as walking. Anti-nerve growth factor (NGF) antibodies have recently shown analgesic effects in OA patients. We examined the effect of a single dose of anti-NGF antibody on pain during motion, joint edema and lesion in a rat model of OA to determine whether the analgesic effect demonstrated in clinical studies can be translated to a preclinical model. Methods: Sodium monoiodoacetate (MIA)-induced arthritic rats that develop a right-left gait imbalance when walking as an index of pain during motion. This imbalance was assessed using a gait analysis system called "CatWalk". Edema size and lesion score in the relevant knee joint were also measured. The effect of a single intravenous injection of an anti-NGF monoclonal antibody AS2886401-00 on these parameters was assessed. Results: AS2886401-00 administered at 0.3 or 1 mg/kg on Day 3 post-MIA injection resulted in a statistically significant improvement in gait imbalance even on Day 35. When gait measurement was set on Week 3 post-MIA administration, administration of the antibody at a timing close to the gait measurement, i.e., 1 or 24 h prior to the measurement, was less effective. AS2886401-00 did not suppress either edema or lesion. Conclusions: A single dose of anti-NGF antibody exerts a long-lasting analgesic effect on pain during motion in a rat model of OA. This finding could be associated with the analgesic efficacies that anti-NGF antibodies have exhibited in clinical studies. It appears unlikely that analgesia is secondary to inhibition of joint edema and lesion. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Serotonin (5-HT) and norepinephrine (NE) have been implicated in the mediation of endogenous analgesic mechanisms via the descending inhibitory pain pathway in the brain, and dysfunction in both the 5-HT and NE systems has been suggested as an etiology of fibromyalgia (FM). Given that 5-HT reuptake inhibition in the brain appears to be associated with pain reduction, this mechanism might exert an analgesic effect also on pain associated with FM. In this case, it would be of interest to investigate the correlation of 5-HT transporter (SERT) occupancy with in vivo analgesic effect on pain associated with FM. Here, we investigated the relationship between SERT occupancies and the analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine, which are both 5-HT and NE reuptake inhibitors (SNRIs), on muscular pain in reserpine-induced myalgia (RIM) rats, an animal model of FM-like chronic pain. We also investigated the SERT occupancy level necessary for AS1069562 and duloxetine to exert analgesic effects on muscular pain. AS1069562 and duloxetine attenuated muscular hyperalgesia in RIM rats, representing the first findings to be reported regarding the analgesic effect of AS1069562 on pain associated with FM. SERT occupancy levels of AS1069562 and duloxetine increased in both dose- and plasma and brain concentration-dependent manners. SERT occupancy levels of AS1069562 and duloxetine were significantly correlated with efficacy on muscular pain thresholds in RIM rats. This finding concerning the precise correlation of SERT occupancy with in vivo analgesic effect on pain associated with FM is reported here for the first time. SERT occupancy level above 70% was necessary for AS1069562 and duloxetine to exert significant analgesic effects on muscular pain. These results suggest that SERT occupancy level is useful in determining appropriate analgesic doses of AS1069562 and duloxetine for treating pain symptoms in FM patients. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

'Dysfunctional pain', a type of chronic pain, is associated with a broad range of clinical disorders, including fibromyalgia, irritable bowel syndrome and interstitial cystitis. It is emerging as a serious issue due to the negative impact of inexplicable pain on quality of life, lack of effective therapies and health care cost. Although drug discovery efforts in pain research have so far focused primarily on inflammatory and neuropathic pain, this editorial attracts attention to dysfunctional pain research and discusses a possible fundamental framework for tackling this difficult issue. While dysfunctional pain is characterized by chronic widespread or regional pain symptoms and occurrence of pain amplification, underlying pathophysiologies remain to be identified. Thus, a pivotal step in future research would be the exploration of pathophysiological pathways, such as relevant molecular networks, which are responsible for dysfunctional pain. Utilization of developing technologies paves the way for the identification of underlying pathophysiologies and the development of effective drugs which would eventually solve the clinical issues associated with dysfunctional pain.

Patients with osteoarthritis (OA) suffer from joint pain aggravated by movement, which affect their quality of life. In the present study, a weight bearing paradigm for pain at rest and a gait paradigm for pain during movement were tested in rats with unilateral knee arthritis induced by an intra-articular injection of sodium monoiodoacetate (MIA). At week 3 after MIA (1 mg/knee) injection, animals developed pain-associated, right-left imbalances of weight distribution (weight bearing) or foot print parameters (gait). Diclofenac, at doses up to 30 mg/kg orally (p o.), did not have a significant effect on either paradigm. Morphine rectified the weight bearing and gait imbalances at 1 and 3 mg/kg subcutaneously, respectively. The weak opioid and serotonin/norepinephrine reuptake inhibitor (SNRI) tramadol also significantly corrected the indices at 10 mg/kg (weight bearing) and 100 mg/kg p.o. (gait). The SNRI duloxetine at 30 mg/kg p.o corrected the weight bearing imbalance but not gait imbalance. We assessed the effect of different drugs on pain-induced disturbances in weight distribution and gait in MIA-induced arthritic rats. Analgesic drugs, each with different mechanisms of action, were less effective in rectifying the imbalance in gait than that in weight distribution. The assessment of the effect of analgesics on not only rest pain but pain during movement is valuable for the comprehensive examination of their therapeutic efficacies in OA. (C) 2014 Elsevier B.V. All rights reserved.

Fibromyalgia is a prevalent musculoskeletal disorder characterized by chronic widespread pain that significantly reduces quality of life in patients. Due to the lack of consistently effective treatment, the development of improved therapies for treating fibromyalgia is necessary. As dysfunction of serotonergic analgesic control appears to be involved in the pathophysiology of fibromyalgia, the present study explored the potential of 5-HT2C receptor agonists as novel therapies for treating this disease. Three 5-HT 2C receptor agonists (lorcaserin, vabicaserin and YM348) that have been suggested to be useful in the treatment of several central nervous system diseases, including obesity and schizophrenia, were used. The effect of systemic administration of these agents on the muscular hyperalgesia that develops in the reserpine-induced myalgia (RIM) rat, a putative animal model of fibromyalgia, was investigated. RIM rats exhibited decreased muscle pressure thresholds. Microdialysis experiments showed that the concentration of serotonin (5-HT) in the spinal cord of RIM rats was significantly lower than that of controls. Lorcaserin (0.3-3 mg/kg p.o.), vabicaserin (0.3-3 mg/kg s.c.) and YM348 (0.03-0.3 mg/kg p.o.) recovered the muscle pressure threshold. The effect of lorcaserin was reversed by the pretreatment with SB242084, a 5-HT 2C receptor antagonist. Our findings demonstrate that 5-HT 2C receptors play a critical role in muscular hyperalgesia in RIM rats and suggest that 5-HT2C receptor agonists have therapeutic potential for treating chronic pain in patients with fibromyalgia although clinical extrapolation remains to be a future challenge. © 2013 Elsevier Inc.

Background The withdrawal response elicited by a nociceptive stimulus, i.e., evoked pain measure, is commonly used as an efficacy endpoint in neuropathic pain animal models. It, however, has several limitations, which highlight the importance of examining spontaneous pain. The present study describes an automated method for measuring spontaneous pain behaviour in a rat model of neuropathic pain caused by chronic constriction injury (CCI) of sciatic nerve. Methods After CCI surgery, a small magnet was implanted into the operated limb. The rat was placed in a test chamber that was surrounded by wire coil. Limb movements, including lifting/guarding, flinching/shaking, licking and walking in the operated limb, caused changes in the electromagnetic field, including a change in voltage and transformed into a signal via an amplifier. Results CCI rats consistently showed more frequent limb movement than sham rats. There was no significant correlation between the frequency of spontaneous pain behaviour and the evoked pain symptoms. Treatment with duloxetine (30?mg/kg p.o.) and amitriptyline (30 and 100?mg/kg p.o.) significantly reduced this frequency. Pregabalin at 30?mg/kg p.o. tended to reduce the frequency, and diclofenac up to 10?mg/kg p.o. had no effect. Conclusion A non-subjective automated method for measuring spontaneous pain behaviour in an animal model of neuropathic pain was established. It is expected that the current system will greatly enhance the analysis of spontaneous pain-related behaviour, which is a predominant symptom in patients with neuropathic pain. The current system may also be valuable in the screening of potential analgesic treatments.

The reserpine-induced myalgia (RIM) rat manifests fibromyalgia-like chronic pain symptoms. The present study explored the pathophysiology underlying the pain symptoms in the RIM rat and the chronic constriction injury (CCI) rat, an animal model of neuropathic pain as a reference. Nerve tissue samples were collected from the nociception-tested animals for pathological examinations. Additionally, the therapeutic efficacy of a sodium channel blocker mexiletine was assessed in both rats. A slight vacuolization in the substantia nigra (SN) occurred in some of the RIM rats without any other histopathological changes in the brain or peripheral neurons. All the RIM rats, with or without vacuolization, showed hypersensitivity to tactile, muscle pressure, and cold stimuli. In the CCI rat, neurodegenerative changes were apparent in the sciatic nerve and the spinal cord only. CCI rats displayed muscle hyperalgesia in addition to tactile and cold allodynia. Pharmacotherapy with mexiletine did not attenuate the pain in the RIM rat, although it was effective in the CCI rat. Taken together, it is not likely that pain symptoms in RIM rats are caused by degenerative changes at the level of primary afferents and spinal cord, as is the case for CCI rats. The significance of the vacuolization in the SN is less clear at present because of the minor extent of the change and the lack of correlation with nociceptive sensitivity. The pain symptoms in RIM rats could be associated with dysfunction of biogenic amines-mediated CNS pain control even without apparent pathologies in the nervous system. (C) 2011 Elsevier B.V. All rights reserved.

The paradigm of sine-wave electrical stimuli has been used for sensory neurological assessment in humans. In the present study, we applied the paradigm to the dog for the quantitative assessment of sensory function. Sine-wave electrical current stimuli at frequencies of 2000, 250, and 5 Hz were delivered to bipolar electrodes attached to the skin surface of the hind paws. The stimulation intensity was gradually increased, and the minimum intensity required to elicit the lifting behavior in the stimulated paw was determined as current threshold (CT) for each of the three frequencies. Dogs consistently showed the lifting behavior at CTs without showing aversive behaviors such as vocalization and wriggling. The baseline CTs (mean +/- SEM, n = 12) were 4430 +/- 110 mu A for CT2000, 2215 +/- 173 mu A for CT250, and 2305 +/- 152 mu A for CT5. The CTs immediately increased after bolus intravenous injection of fentanyl at 10 mu g/kg, although the significant increase disappeared within 1 h. The time course for the as was parallel to that of plasma fentanyl concentration. In conclusion, the present study applied the paradigm of transcutaneous sine-wave electrical stimuli to the dog, and used the hind paw lifting as endpoint behavior. This paradigm is simple, non-invasive, useful in the assessment of sensory function, and can be adapted to investigate the pharmacokinetics/pharmacodynamics relation of drugs. Further studies are needed to give the conclusive interpretation of the endpoint behavior. (C) 2010 Elsevier Inc. All rights reserved.

The present study investigated the precise relationship between brain biogenic amine (dopamine, noradrenaline, and serotonin) tones and nociception. Nociceptive sensitivities to multimodal (muscle pressure, tactile, cold, and heat) stimuli were assessed in acute phase (up to 24 h after reserpine or tetrabenazine injection) and chronic phase (on day 2 or later) in rats. A single injection of reserpine (3 mg/kg s.c.) significantly decreased biogenic amines in the spinal cord (SC), thalamus (THA), and prefrontal cortex (PFC) in both acute and chronic phases, but significantly increased a dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the SC and a serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the SC and THA in acute phase. The content of all biogenic amine metabolites was at low level in chronic phase. Animals exhibited hypersensitivities to tactile and heat stimuli and hyposensitivity to muscle pressure stimulus in acute phase. In chronic phase, they manifested hypersensitivities to all modes of stimuli. Tetrabenazine (20 mg/kg i.p.) significantly decreased brain biogenic amines for a short time, although it did not significantly affect the nociceptive sensitivities. In conclusion, a single injection of reserpine causes a biphasic alteration of nociceptive sensitivities, which is in conjunction with the dynamic change of brain biogenic amine tones, in rats. Cold and heat hypersensitivities in addition to mechanical ones are induced by the reserpine treatment. Sustained modification of brain biogenic amine tones would be critical to induce a robust change in nociceptive sensitivities based on the different effects between reserpine and tetrabenazine. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Fibromyalgia is a prevalent and burdensome disorder characterized by chronic widespread pain and complex comorbid symptoms. To develop better treatments for pain-centered fibromyalgia symptoms, there is still a need for animal models which mimic the features of fibromyalgia patients. In the present study, we have established a fibromyalgia animal model by utilizing a never-before-published pharmacological effect of reserpine. Repeated administration of reserpine (1 mg/kg s.c., once daily, for three consecutive days) causes a significant decrease in the muscle pressure threshold and tactile allodynia, which are sustained for 1 week or more in both male and female rats. This treatment regimen decreases the amount of biogenic amines (dopamine, norepinephrine, and 5-hydroxytryptamine) in the spinal cord, thalamus, and prefrontal cortex, which are deeply involved in pain signal processing. It also significantly increases immobility time in the forced swim test, which is indicative of depression, a common comorbid symptom of fibromyalgia. Pregabalin, duloxetine, and pramipexole significantly attenuated the reserpine-induced decrease in muscle pressure threshold, but diclofenac did not. The validity of the use of this reserpinized animal as a fibromyalgia model is demonstrated from three different aspects, i.e., face validity (manifestation of chronic pain and comorbid symptoms), construct validity (dysfunction of biogenic amine-mediated central nervous system pain control is involved), and predictive validity (similar responses to treatments used in fibromyalgia patients). This animal model is expected to contribute to the better understanding of fibromyalgia pathophysiology and the evaluation of drugs, especially those which would activate biogenic amine system. (C) 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Further understanding of pathophysiology of postoperative acute pain is necessary for its better management. The methodology Of Current threshold (CT) determination by using sine-wave stimuli at 3 frequencies has been used to selectively and quantitatively analyze the function of the subsets of fibers (i.e., frequency of 5, 250, and 2000 Hz recruits C-, A delta-, and A beta-fibers, respectively). This study investigated how surgical incision would affect the CTs, and then assessed the efficacy of intrathecal pharmacotherapy. The CT required to evoke a paw withdrawal response was assessed over time at Stimulus frequencies of 5 Hz (CT5), 250 Hz (CT250), and 2000 Hz (CT2000) in rats that had undergone surgical incision of the plantar skin and muscle. The CTs at all frequencies significantly decreased immediately after the incision. The decreased thresholds gradually recovered during the first week post-surgery. CT5 and CT250 (but not CT2000) remained significantly low even on day 7 post-surgery. Morphine at 5 mu g/10 mu L i.t. significantly reversed CT5 and CT250. NBQX (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]kainate receptor antagonist) at 1.9 or 3.8 mu g/10 mu L- i.t. significantly increased the thresholds over the pre-surgery threshold levels at all frequencies. MK-801 (N-methyl D-aspartate [NMDA] receptor antagonist) up to 13.5 mu g/10 mu L i.t. did not significantly affect CTs at any frequencies. In conclusion, a broad spectrum of sensory fibers (A beta, A delta,.and C) is sensitized at the spinal and/or peripheral level in the postoperative acute pain state. Spinal AMPA/kainate receptors but not NMDA receptors play a significant role in this sensitization. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

The P2X(2/3) receptor has an important role in the nociceptive transmission. Minodronic acid is a third third-generation bisphosphonate and a potent inhibitorofbone resorption. We found that minodronic acid inhibited alpha,beta-methylene ATP-induced cation uptake with the potency higher than that of suramin in the P2X(2/3) receptor receptor-expressing cells. Other bisphosphonates did not show such activity. Subcutaneously administered (10-50 mg/kg) minodronic acid significantly inhibited the alpha,beta-methylene ATP-, acetic acid- and formalin-induced nociceptive behaviors in mice. These unique effects of minodronic acid would be beneficial for the treatment of accelerated bone turnover diseases accompanied by bone pain, including bone metastases. (C) 2008 Elsevier B.V. All rights reserved.

Electrical stimulation is widely used to assess the function of sensory nerves in humans. In the present study, the threshold current (CT) required to evoke a paw withdrawal response in rats was assessed with stepwise increases in current delivered as sinusoidal stimulation at frequencies of 2000 Hz (CT2000), 250 Hz (CT250) and 5 Hz (CT5). Baseline CT was 840 +/- 3 mu A for CT2000, 267 +/- 2 mu A for CT250 and 165 +/- 1 mu A for CT5 (n = 59). Intrathecal administration (1-10 mu g/rat) of morphine selectively increased CT5 and CT250 (efficacy order was CT5 > CT250 > CT2000 = 0), although systemic morphine (1-5 mg/kg, S.C.) affected all three CTs (CT5 > CT250 > CT2000 > 0). Intrathecal pretreatment at day -3 of capsaicin (75 mu g/rat) increased the thermal nociceptive threshold and selectively increased CT5 (CT5 > CT250, CT2000 = 0). Intraplantar carrageenan injection progressively decreased CT250 and CT5, but increased CT2000 for a 3 h period. Intraperitoneal pretreatment with indomethacin (20 mg/kg) attenuated carrageenan evoked CT alterations as well as progression of paw swelling and thermal hyperalgesia. In conclusion, low, but not high, frequency stimulation activated a withdrawal response which appears mediated by morphine and capsaicin sensitive primary afferents and this threshold was reduced in the presence of inflammation. These data suggest the validity of such stimulation in defining drug action in a nontissue injurious fashion. (c) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Metabotropic glutamate receptor 1 (mGlu (1)receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu(1) receptor blockade. YM-230888 bound an allosteric site of mGlu(1) receptor with a K-i value of 13 +/- 2.5 nM and inhibited mGlu(1)-mediated inositol phosphate production in rat cerebellar granule cells with an IC50 value of 13 +/- 2.4 nM. It showed selectivity for mGlu(1) versus mGlu(2)-mGlu(7) subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED50 value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlul receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions, In addition, YM-230888 may be a useful tool for the investigation of mGlu(1) receptors. (c) 2007 Elsevier B.V. All rights reserved.

Background and purpose: Despite the rapid progress made in understanding the significant role played by signalling via extracellular ATP in physiology and pathology, there has been no clear information generated on its involvement in the emetic response. Experimental approach: In the present study, the emetogenic potential of extracellular ATP signalling in mammalian species was examined using ferrets and Suncus murinus ( house musk shrews). A slowly degradable ATP analogue, alpha, beta-methyleneATP (alpha,beta- meATP), was used to activate the P2X receptors, and either the non- selective P2 receptor antagonist, pyridoxal phosphate-6-azophenyl- 2',4'-disulphonic acid ( PPADS), or the specific P2X(3) homomer and P2X(2/3) heteromer antagonist, A- 317491, were tested against the agonist- induced response. Key results: Intraperitoneal injection of alpha, beta- meATP produced significant emetic responses in ferrets ( 1 - 30 mg kg(-1)) and in Suncus murinus ( 5 - 50 mg kg(-1)). The responses occurred frequently within the first 10 min after administration, much less frequently from 11 to 60 min and no responses occurred later than 60 min. The emetic responses were completely inhibited by intraperitoneal pre- treatment with PPADS ( 100 mg kg(-1)) or A- 317491 ( 100 mg kg(-1)). Abdominal surgical vagotomy did not reduce the emetic response in Suncus murinus significantly. Conclusions and implications: These results for the first time indicate that the activation of P2X receptors evokes emetic responses in mammalian species. The P2X(3) homomer and . or P2X(2/3) heteromer in the area postrema could be responsible for the emetic response. This finding contributes to the elucidation of the roles played by extracellular ATP signalling in various emetic symptoms.

Metabotropic glutamate receptor type 1 ( mGluR1) is thought to play important roles in the neurotransmission and pathogenesis of several neurological disorders. Here, we describe the radioligand binding properties and pharmacological effects of a newly synthesized, high-affinity, selective, and noncompetitive mGluR1 antagonist, 6-amino-N-cyclohexyl-N, 3-dimethylthiazolo[3,2-a] benzimidazole-2-carboxamide (YM-298198). YM-298198 inhibited glutamate-induced inositol phosphate production in mGluR1-NIH3T3 cells with an IC50 of 16 +/- 5.8 nM in a noncompetitive manner. Its radiolabeled form, [H-3] YM298198, bound to mGluR1-NIH3T3 cell membranes with a K D of 32 +/- 8.5 nM and a B-max of 2297 +/- 291 fmol/mg protein. In ligand displacement experiments using rat cerebellum membrane, an existing noncompetitive mGluR1 antagonist 7-( hydroxyimino) cyclo-propa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) competitively displaced [H-3]YM-298198 binding, although glutamate and other mGluR1 ligands acting on a glutamate site failed to inhibit [H-3]YM-298198 binding, suggesting that YM-298198 binds to CPCCOEt ( allosteric) binding sites but not to glutamate ( agonist) binding sites. Specificity was demonstrated for mGluR1 over mGluR subtypes 2 to 7, ionotropic glutamate receptors, and other receptor, transporter, and ion channel targets. In in vivo experiments, orally administered YM-298198 showed a significant analgesic effect in streptozotocin- induced hyperalgesic mice at doses (30 mg/kg) that did not cause Rotarod performance impairment, indicating that it is also useful even for in vivo experiments. In conclusion, YM-298198 is a newly synthesized, high-affinity, selective, and noncompetitive antagonist of mGluR1 that will be a useful pharmacological tool due to its highly active properties in vitro and in vivo. Its radiolabeled form [H-3]YM-298198 will also be a valuable tool for future investigation of the mGluR1.

The complete Freund's adjuvant (CFA)-induced arthritic rat model has extensively served as a laboratory model in the study of arthritic pain. However, the time courses of allodynia and hyperalgesia and the efficacies of different analgesics have not fully been analyzed in this model. Mechanical allodynia, thermal and joint hyperalgesia, and other disease development parameters (body weight, mobility, paw volume, and joint stiffness) were measured on postinoculation days (PIDs) 0 to 28 in rats. Acute analgesic efficacies of drugs were evaluated on PID 9 when degrees of allodynia, hyperalgesia, and joint stiffness in the ipsilateral paw reached almost the maximum, although those in the contralateral paw changed only slightly. In the ipsilateral paw, thermal hyperalgesia reached the maximum on PID 1, whereas mechanical allodynia and joint hyperalgesia progressively developed during the first 7 or 8 days, being tuned in to arthritis development. In the contralateral paw, thermal hyperalgesia never occurred, whereas mechanical allodynia and joint hyperalgesia developed after PID 11. Morphine and tramadol had full efficacies for all the pain parameters tested at sedation-inducing doses. Indomethacin and diclofenac significantly but partially improved thermal and joint hyperalgesia. Amitriptyline significantly reduced thermal and joint hyperalgesia only at sedation-inducing dose. Acetaminophen, carbamazepine, and gabapentin had, at the most, very small efficacies. In conclusion, the present study provided integrated information about the time course of pain and other disease development parameters in the CFA-induced arthritic rats, and clarified acute efficacies of different categories of analgesics for the allodynia and hyperalgesia.

The effect of the selective 5-hydroxytryptamine (5-HT)(3) receptor agonist YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate) on gut motility of fed ferrets was investigated. YM-31636 (0.1 mg/kg p.o.) induced a giant migrating contraction (GMC)-like, high-amplitude, ungrouped colonic contraction although it did not change the basal colonic motility pattern. This GMC-like contraction was always accompanied by defecation. Both GMC-like contraction and defecation were inhibited with the selective 5-HT3 receptor antagonist ramosetron. YM-31636 affected gastric, duodenal and ileal motility pattern only slightly. These results suggest that 5-HT3 receptor agonists such as YM-31636 are useful in treating constipation since they facilitate GMC-like contractions and defecation without undesired changes in gut motility pattern. (C) 2002 Elsevier Science Inc. All rights reserved.

We examined the current stimulus threshold in rats with the Neurometer, a device used clinically for measuring perception and pain thresholds. Although many studies have indicated the usefulness of this device in the quantification of nerve dysfunction in patients, we have found no published reports on the use of the Neurometer in animals. Transcutaneous nerve stimuli of the three sine-wave pulses produced by the Neurometer (at 2000, 250, and 5 Hz) were applied to plantar surface of rats. The intensity of each stimulation at which rats vocalized or were hardly startled was defined as the current stimulus threshold. With repeated stimulation, the thresholds were almost constant. Repeated topical application to the area around the stimulating electrode of a high concentration of capsaicin, which acts on small-diameter fibers, increased the thresholds at 250 and 5 Hz, but did not affect the 2000-Hz threshold. Intravenous morphine (2-5 mg/kg) increased all three thresholds, whereas intrathecal morphine (20 or 80 mug) increased only the 5-Hz threshold. Intravenous injection of a minor tranquilizer, diazepam, at 1 mg/kg raised the thresholds at 2000 and 250 Hz, but did not affect the 5-Hz threshold. Higher dose of diazepam increased all three thresholds. These results suggest that the Neurometer makes possible selective examination of subsets of nerve fibers that differ in diameter not only in humans but also in animals. The present study in rats, in which we established a method of measurement, may provide helpful suggestions for the interpretation of data in humans.

We investigated the in vitro pharmacological profile of YM-31636 (2-(1 H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate). In cloned human 5-HT3A receptors, YM-31636 had a p K-i value of 9.67 vs, ramosetron and p K-i values for other 5-HT3 receptor agonists were less than 7. YM-31636 showed very low affinities far other receptors. YM-31636 induced contraction of isolated guinea pig distal colon. The intrinsic activity was approximately 0.90 compared with 5-hydroxytryptamine's (5-HT) 1.0, and the potency was 26 times greater than that of 5-HT. YM-31636 increased short-circuit current (I-sc) in the isolated guinea pig distal colon. In this case, the relative intrinsic activity was approximately 0.19. In isolated guinea gig right atrium, YM-31636 induced tachycardia with the relative intrinsic activity of approximately 0.23. All these effects of YM-31636 were antagonized by ramosetron, a selective 5-HT, receptor antagonist. These results suggest that YM-31636 is a potent and selective S-HT3 receptor agonist, preferentially acting on the contraction of the colon. (C) 2000 Elsevier Science B.V. All rights reserved.

The role of 5-hydroxytryptamine (5-HT)(3) and 5-HT4 receptors in the regulation of gut motility in the ferret was investigated. The selective 5-HT3 receptor antagonist ramosetron (1 - 10 mu g/kg s.c.) prolonged the interval of gastric antral migrating motor complex, but had only slight effect on small intestinal and colonic motility in unfed animals. The selective 5-HT4 receptor antagonist SE 204070 did not affect motility throughout gut in unfed animals. Neither ramosetron nor SE 204070 affected the motility throughout gut in fed animals. In conclusion, neither 5-HT3 nor 5-HT4 receptors tonically regulate ferret gut motility except that 5-HT3 receptors have a key role in the occurrence of migrating motor complex specifically in the stomach. The role of 5-HT3 and 5-HT4 receptor system in the regulation of gut motility in ferrets is similar to that in other mammalian species studied, including humans. This similarity suggests that the ferret is a suitable model animal to study gut motor functions in humans. (C) 2000 Elsevier Science Inc.

The effect of neuroactive progesterone metabolites, 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one, and their stereoisomers at the 3 C site, 5 alpha- and 5 beta-pregnan-3 beta-ol-20-one, on gastric acid secretion was investigated in urethane-anesthetized rats. Both 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one dose-dependently (0.3-3 mg.kg(-1), i.v.) stimulated gastric acid secretion with an early onset of action. Their potency and efficacy were almost the equivalent of one another. In contrast, their stereoisomers did not have asignificant effect even at 10 mg.kg(-1) (i.v.). The 5 beta-pregnan-3 alpha-ol-20-one (3 mg.kg(-1), i.v.)-stimulated gastric acid secretion was remarkably inhibited by bilateral vagotomy or pretreatment with atropine (1 mg.kg(-1), i.v.). An antagonist of the GABA(A) receptor, picrotoxin, at 3 and 6 mg.kg(-1) (i.v,), significantly inhibited the 5 beta-pregnan-3 alpha-ol-20-one (3 mg.kg(-1), i.v.)-stimulated gastric acid secretion. These results indicate that naturally occurring neuroactive steroids, 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one, stimulate gastric acid secretion in a stereoselective and dose-dependent manner in urethane-anesthetized rats. It is likely that the action of these neuroactive steroids is of central origin and that interaction with GABA(A) receptors and stimulation of vagal pathway are involved in its mechanism of action. (C) 2000 Elsevier Science Ltd. Published by Editions scientifiques et medicales Elsevier SAS.

Binding properties of gastrointestinal prokinetic benzamides for both cloned human 5-hydroxytryptamine (5-HT)(3) receptors and cloned human 5-HT4 receptors were examined and pharmacological properties of YM-53389{(+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperid methyl)-1,2,4-oxadiazol-3-yl]aniline monohydrochloride} were characterised in animals. Cisapride, renzapride and zacopride inhibited specific binding of [H-3]ramosetron to cloned human 5-HT3 receptors, with K-i values of 684, 7.64 and 0.38 nM, respectively. YM-53389, however, slightly replaced that (K-i > 10,000 nM). YM-53389, cisapride, renzapride and zacopride replaced specific binding of [H-3]GR 113808 to cloned human 5-HT,receptors, with K-i, values of 54.6, 41.5, 115 and 373 nM, respectively. The potency for inhibitory effect of YM-53389 on 5-HT4 receptor-mediated contraction in the guinea-pig isolated colon was very low with pIC(50) of 4.7. YM-53389 exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat isolated oesophagus with pEC(50) of 6.3. In mice, YM-53389 at 10 and 30 mg kg(-1) s.c. significantly shortened whole gut transit time, in contrast to cisapride, renzapride and zacopride which were reported to delay that. YM-53389 had no significant effect on upper gastrointestinal propulsion at doses up to 30 mg kg(-1), s.c. Based on these results, YM-53389 may surpass existing benzamides in facilitating lower intestinal propulsion and benefit patients with gastrointestinal disorders associated with impair of intestinal propulsion, such as constipation, based on the selective interaction with human 5-HT4 receptors vs human 5-HT3 receptors. (C) 1999 Academic Press.

In a search for novel 5-hydroxytryptamine 4 (5-HT4) agonists focusing on the linker group of benzamide derivatives, 2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)- 1,2,4-oxadiazol-3-yl] aniline (2) was prepared and its optical isomers were separated. The S isomer 2(S) showed high affinity for the human 5-HT4 receptor without affinity for the human 5-HT3 receptor, and potent 5-HT4 agonistic activity in longitudinal muscle myenteric plexus (LMMP) preparations of guinea pig ileum. The R isomer 2(R) showed opposite selectivity. As a result of other receptor binding studies, 2 (S) (YM-53389) was shown to be a highly selective 5-HT4 agonist.

The influence of diabetic hyperglycemia on solid gastric emptying in rats was examined. Diabetes was produced by streptozotocin (STZ, 40 mg/kg i.v.), and diabetic hyperglycemia was observed from 1 day after the STZ injection. The gastric emptying of glass beads in the diabetic rats was significantly delayed compared with that in age-matched control rats at 1, 3 and 7 days after diabetes induction. A slight decrease in gastric emptying was observed in the diabetic rats from 2 to 52 weeks after the diabetes induction. We also investigated the influence of gastroprokinetic agents on STZ-induced diabetic gastroparesis and subdiaphragmatic vagotomy-induced gastroparesis in rats. The selective 5-HT3 receptor antagonists ramosetron (YM060), YM114 (KAE-393), granisetron and ondansetron, and the substituted benzamides (5-HT4 receptor agonist/5-HT3 receptor antagonists) cisapride mosapride and SC-53116 dose-dependently enhanced gastric emptying in normal rats. These compounds also reversed the impairment of diabetic gastroparesis rats at 7 days after the STZ injection, but higher doses were required. The solid gastric emptying in subdiaphragmatic vagotomized rats was also delayed. Ramosetron and the substituted benzamides cisapride and zacopride partially reversed the gastroparesis in the vagotomized rats. These results suggest that acute hyperglycemia is important mechanism for the delay of solid gastric emptying in diabetic rats. It is also suggested that selective 5-HT3 receptor antagonists and substituted benzamides enhance gastric emptying not only in normal rats but also in diabetic and vagotomized rats.

Interactions of gastrointestinal prokinetic benzamides with 5-hydroxytryptamine (5-HT)(3) and 5-HT4 receptors and the relation to their effects on gastrointestinal propulsion were investigated. Renzapride and zacopride potently inhibited 5-HT3-receptor-mediated contractions in the guinea pig colon, whereas RS67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-sulphonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride), a selective 5-HT4-receptor agonist, showed no inhibition. RS67506, renzapride and zacopride all exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat oesophagus. In mice, RS67506 shortened the whole gut transit time, whereas renzapride and zacopride were reported to prolong it. Gastrointestinal prokinetic benzamides, which are selective for 5-HT4-receptor agonistic over 5-HT3-receptor antagonistic action, may be useful in treating gastrointestinal disorders associated with impaired lower intestinal propulsion such as constipation.

The effect of m-chlorophenylbiguanide, a selective 5-HT3 receptor agonist, on gastric antral motility was investigated in conscious dogs with a force transducer implanted chronically. m-Chlorophenylbiguanide (0.1-1 mg/kg i.v.) dose dependently enhanced antral motility in the fasted state, and the amplitude of m-chlorophenylbiguanide (1 mg/kg i.v.)-induced antral contractions reached the level of natural phase III contractions. In contrast, m-chlorophenylbiguanide reduced the amplitude of antral contractions in the fed state. A selective 5-HT3 receptor antagonist, ramosetron (0.0003-0.03 mg/kg i.v.), inhibited both effects of m-chlorophenylbiguanide. m-Chlorophenylbiguanide (1 mg/kg i.v.)-induced contractions were inhibited by atropine (0.03 or 0.1 mg/kg i.v.). These results indicate that pharmacological activation of 5-HT3 receptors has opposite effects on canine gastric antral motility in the fasted and in the fed state, being stimulatory and inhibitory, respectively. The stimulatory effect seems to be mediated mainly via the release of acetylcholine.

Gastrointestinal motility was measured with force transducers in conscious ferrets. The gastrointestinal motility pattern in both the interdigestive and digestive states was similar to that reported for humans. The activity front, phase III contractions of the migrating motor complex, occurred cyclically in the antrum and migrated to the duodenum and ileum in the interdigestive state, and relatively low-amplitude contractions were sustained in the antrum, duodenum and ileum in the digestive state. Colonic motility was characterized by basal relatively low-amplitude contractions and a single high-amplitude contraction preceding defecation. Cisapride (0.3-3 mg/kg s.c.) enhanced antral and colonic motility. This ferret model will help the investigation and evaluation of drug effects on gastrointestinal motility in humans. (C) 1997 Elsevier Science B.V.

The influence of diabetic hyperglycemia on solid gastric emptying in rats was examined. Diabetes was produced by streptozotocin (STZ, 40 mg/kg i.v.), and diabetic hyperglycemia was observed from 1 day after the STZ injection. The gastric emptying of glass beads in the diabetic rats was significantly delayed compared with that in age-matched control rats at 1, 3 and 7 days after diabetes induction. A slight decrease in gastric emptying was observed in the diabetic rats from 2 to 52 weeks after the diabetes induction. We also investigated the influence of gastroprokinetic agents on STZ-induced diabetic gastroparesis and subdiaphragmatic vagotomy-induced gastroparesis in rats. The selective 5-HT3 receptor antagonists ramosetron (YM060), YM114 (KAE-393), granisetron and ondansetron, and the substituted benzamides (5-HT4 receptor agonist/5-HT3 receptor antagonists) cisapride mosapride and SC-53116 dose-dependently enhanced gastric emptying in normal rats. These compounds also reversed the impairment of diabetic gastroparesis rats at 7 days after the STZ injection, but higher doses were required. The solid gastric emptying in subdiaphragmatic vagotomized rats was also delayed. Ramosetron and the substituted benzamides cisapride and zacopride partially reversed the gastroparesis in the vagotomized rats. These results suggest that acute hyperglycemia is important mechanism for the delay of solid gastric emptying in diabetic rats. It is also suggested that selective 5-HT3 receptor antagonists and substituted benzamides enhance gastric emptying not only in normal rats but also in diabetic and vagotomized rats.

The role of 5-HT3 receptors in the control of intestinal propulsive activity was investigated in mice by a simple method in which the time taken for excretion of the head of an orally administered non-absorbable marker (whole gut transit time) was measured, Selective 5-HT3 receptor antagonists ramosetron (YM060) at 0.01-0.3 mg/kg s.c. and ondansetron at 0.1-1 mg/kg s.c. dose-dependently prolonged the whole gut transit time. Prokinetic benzamides, such as renzapride (0.3-10 mg/kg s.c.), zacopride (0.01-0.3 mg/kg s.c.) and cisapride (0.1-3 mg/kg s.c.), which have been reported to possess 5-HT3 receptor blocking properties, also dose-dependently prolonged it. These results indicate that activation of 5-HT3 receptors seems to be one factor that underlies the physiological control of intestinal propulsive activity in mice. In contrast to their beneficial therapeutic effects on gastroduodenal dysmotility, prokinetic benzamides, at least those which have 5-HT3 receptor antagonistic activity, may be unsuitable in the treatment of impaired lower intestinal propulsive activity.

We examined the effects of exogenous 5-hydroxytryptamine (5-HT) and selective 5-HT receptor agonists and antagonists on proximal, middle and distal colonic motility in conscious fasted dogs with extraluminal force transducers implanted chronically. 5-HT (0.003-0.1 mg/kg i.v.) dose-dependently enhanced motility along the entire length of the colon. The 5-HT (0.03 mg/kg i.v.)-induced response was inhibited by 0.1-1.0 mg/kg i.v. methysergide, a 5-HT1/2 antagonist, at all recording sites and by 0.1-1.0 mg/kg i.v. ketanserin, a 5-HT2A antagonist, at the middle and distal sites only. At 1 mg/kg i.v., YM060, a 5-HT3 antagonist, reduced the amplitude of the initial transient high-amplitude contractions induced by 5-HT, but did not affect the tonic contraction induced by 5-HT. At doses up to 3 mg/kg i.v., 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl eater (SDZ205-557),a 5-HT, antagonist, and hexamethonium (up to 10 mg/kg i.v.) did not affect 5-HT-induced responses at any recording site. Renzapride, a 5-HT4 agonist, also stimulated motility along the entire length of the colon at 0.3 mg/kg i.v.. The renzapride-induced response was inhibited by 1 mg/kg i.v. SDZ205-557 or 3 mg/kg i.v. hexamethonium. m-Chlorophenylbiguanide (m-CPBG), a 5-HT3 agonist,(1 mg/kg i.v.) produced a transient high-amplitude contraction at all recording sites and this contraction was eliminated by pretreatment with 0.03 mg/ kg i.v. YM060. The contraction produced by m-CPBG declined rapidly, so the increase in the motility index by m-CPBG was not significant at any recording site. Of the antagonists tested, 0.1-1 mg/kg i.v. methysergide produced a delayed and prolonged contractile response at the middle and distal sites. The onset of the response was delayed about 20 min after application and the response was maintained over the subsequent 60-min observation period. The methysergide (1 mg/kg i.v.)-induced response was inhibited by 3 mg/kg i.v. hexamethonium. The other antagonists, ketanserin, YM060 and SDZ205-557, had no contractile effect at any recording site. These results indicate that exogenous 5-HT stimulates motility along the entire length of the fasted canine colon and that 5-HT-induced responses in the proximal colon are mediated mainly by 5-HT1, whereas those in the middle and distal colon are mediated by both 5-HT and 5-HT2 receptors. Renzapride and methysergide also stimulate colonic motility via additional mechanisms. The activation of 5-HT4 receptors and the blockade of endogenous 5-HT inhibitory regulation via 5-HT1 receptors may be involved in the action of renzapride and methysergide respectively.

Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression. Am. J. Physiol. 269 (Gastrointest. Liver Physiol. 32): G699-G705, 1995.-Female rats were treated orally for 13 wk with YM022 (300 mu mol . kg(-1) day(-1)) and with omeprazole (400 mu mol . kg(-1). day(-1)) or famotidine (900 mu mol . kg(-1). day(-1)) with or without YM022. At 2 h after the last dose, YM022 and omeprazole markedly inhibited basal and pentagastrin-induced acid secretion. Famotidine was less potent than YM022 and omeprazole against both secretions. The degree of increase in plasma gastrin level in the three groups was parallel to the antisecretory potencies of the drugs. At 14 days after the cessation of omeprazole treatment, the secretory response to pentagastrin increased above that of the control. This hyperresponse lasted for greater than or equal to 56 days. In the famotidine-treated group, a small increase in secretory response to pentagastrin was observed but was not statistically significant. The increase in secretory response to pentagastrin was paralleled by an increase in mucosal cell mass. In contrast, YM022 not only exhibited a long-lasting inhibition of pentagastrin-induced acid secretion but also prevented the hyperresponse to pentagastrin caused by omeprazole. These results indicate that the hypergastrinemia caused by long-term administration of antisecretory drugs increases mucosal secretory response to pentagastrin through a gastrin/cholecystokinin B receptor-mediated pathway in rats