resiniferatoxin and Body-Weight

Capsaicin-sensitive afferents have complex regulatory functions in the joints orchestrated via neuropeptides. This study aimed to determine their role in the collagen-antibody induced rheumatoid arthritis model. Capsaicin-sensitive nerves were defunctionalized by the capsaicin receptor agonist resiniferatoxin in C57Bl/6 mice. Arthritis was induced by the ArithroMab antibody cocktail and adjuvant. Arthritis was monitored by measuring body weight, joint edema by plethysmometry, arthritis severity by clinical scoring, mechanonociceptive threshold by plantar esthesiometry, thermonociceptive threshold by hot plate, cold tolerance by paw withdrawal latency from 0 °C water. Grasping ability was determined by the wire-grid grip test. Bone structure was evaluated by in vivo micro-CT and histology. Arthritic animals developed a modest joint edema, mechanical and cold hyperalgesia, weight loss, and a diminished grasping function, while thermal hyperalgesia is absent in the model. Desensitised mice displayed reduced arthritis severity, edema, and mechanical hyperalgesia, however, cold hyperalgesia was significantly greater in this group. Arthritic controls displayed a transient decrease of bone volume and an increased porosity, while bone density and trabecularity increased in desensitised mice. The activation of capsaicin-sensitive afferents increases joint inflammation and mechanical hyperalgesia, but decreases cold allodynia. It also affects inflammatory bone structural changes by promoting bone resorption.

Topics: Animals; Ankle Joint; Antibodies; Arthritis, Experimental; Body Weight; Capsaicin; Disease Models, Animal; Diterpenes; Edema; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Neurons, Afferent; Severity of Illness Index; X-Ray Microtomography

The exacerbation of musculoskeletal pain by stress in humans is modeled by the musculoskeletal hyperalgesia in rodents following a forced swim. We hypothesized that stress-sensitive corticotropin releasing factor (CRF) receptors and transient receptor vanilloid 1 (TRPV1) receptors are responsible for the swim stress-induced musculoskeletal hyperalgesia. We confirmed that a cold swim (26 °C) caused a transient, morphine-sensitive decrease in grip force responses reflecting musculoskeletal hyperalgesia in mice. Pretreatment with the CRF2 receptor antagonist astressin 2B, but not the CRF1 receptor antagonist NBI-35965, attenuated this hyperalgesia. Desensitizing the TRPV1 receptor centrally or peripherally using desensitizing doses of resiniferatoxin (RTX) failed to prevent the musculoskeletal hyperalgesia produced by cold swim. SB-366791, a TRPV1 antagonist, also failed to influence swim-induced hyperalgesia. Together these data indicate that swim stress-induced musculoskeletal hyperalgesia is mediated, in part, by CRF2 receptors but is independent of the TRPV1 receptor.

Topics: Acenaphthenes; Analgesics; Analysis of Variance; Animals; Body Weight; Cold Temperature; Disease Models, Animal; Diterpenes; Female; Hyperalgesia; Mice; Morphine; Muscle Strength; Musculoskeletal Pain; Pain Measurement; Peptide Fragments; Peptides, Cyclic; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Swimming; TRPV Cation Channels

Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non-diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats.. We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL-1β, IL-6 and TNF-α) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue.. From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy.

Topics: Animals; Blood Glucose; Body Weight; Calcitonin Gene-Related Peptide; Capsaicin; Cytokines; Diterpenes; Glucose Tolerance Test; Hyperalgesia; Hyperglycemia; Inflammation Mediators; Injections, Intraperitoneal; Injections, Spinal; Insulin; Microglia; Pain; Posterior Horn Cells; Rats; Streptozocin; TRPV Cation Channels

A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX) binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG), and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diterpenes; Ganglia, Spinal; Hot Temperature; Immunohistochemistry; Injections, Intraperitoneal; Ion Channel Gating; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Pain; Streptozocin; Tritium; TRPV Cation Channels

This study was performed to investigate the effects of goshajinkigan, a traditional Chinese herbal mixture, in conscious rats undergoing continuous cystometry. Systemic resiniferatoxin (RTX) pretreatment can block resiniferatoxin-sensitive (C-fiber) nerve-mediated bladder overactivity, such as that induced by intravesical administration of acetic acid. The effects of pretreatment with goshajinkigan and RTX alone or in combination on acetic acid-induced bladder overactivity in conscious rats were also compared. Female SD rats were divided into four groups. Groups 1 and 3 received normal food for 4 weeks, while groups 2 and 4 received goshajinkigan (0.09 g/kg/day) during the same period. Two days after bladder catheterization, groups 3 and 4 received RTX (0.3 mg/kg) injection, while groups 1 and 2 received vehicle alone. Cystometric investigations were performed on all animals 24 hours after RTX or vehicle injection. The effects of intravesical instillation of acetic acid (pH = 4.0) were compared with those of intravesical saline. Goshajinkigan significantly increased threshold pressure, voiding interval, micturition volume, and bladder capacity. Intravesical instillation of acetic acid induced bladder overactivity in both normal rats and in those pretreated with goshajinkigan. However, the effects of acetic acid on voiding interval and micturition volume were significantly different between rats given normal diet and those pretreated with goshajinkigan. The effect of acetic acid was not different between goshajinkigan- and RTX-pretreated rats. The results of the present study indicated that goshajinkigan increases voiding interval, micturition volume, and bladder capacity, and pretreatment with goshajinkigan partially blocks the bladder overactivity induced by intravesical administration of acetic acid in rats.

Topics: Acetic Acid; Animals; Body Weight; Diterpenes; Drugs, Chinese Herbal; Female; Rats; Rats, Sprague-Dawley; Urinary Bladder

Recent studies have suggested that sensory nerves may influence insulin secretion and action. The present study investigated the effects of resiniferatoxin (RTX) inactivation of sensory nerves (desensitization) on oral glucose tolerance, insulin secretion and whole body insulin sensitivity in the glucose intolerant, hyperinsulinemic, and insulin-resistant obese Zucker rat. After RTX treatment (0.05 mg/kg RTX sc given at ages 8, 10, and 12 wk), fasting plasma insulin was reduced (P < 0.0005), and oral glucose tolerance was improved (P < 0.005). Pancreas perfusion showed that baseline insulin secretion (7 mM glucose) was lower in RTX-treated rats (P = 0.01). Insulin secretory responsiveness to 20 mM glucose was enhanced in the perfused pancreas of RTX-treated rats (P < 0.005) but unaffected in stimulated, isolated pancreatic islets. At the peak of spontaneous insulin resistance in the obese Zucker rat, insulin sensitivity was substantially improved after RTX treatment, as evidenced by higher glucose infusion rates (GIR) required to maintain euglycemia during a hyperinsulinemic euglycemic (5 mU.kg(-1).min(-1)) clamp (GIR(60-120min): 5.97 +/- 0.62 vs. 11.65 +/- 0.83 mg.kg(-1).min(-1) in RTX-treated rats, P = 0.003). In conclusion, RTX treatment and, hence, sensory nerve desensitization of adult male obese Zucker rats improved oral glucose tolerance by enhancing insulin secretion, and, in particular, by improving insulin sensitivity.

Topics: Animals; Body Weight; Diterpenes; Drinking; Eating; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; In Vitro Techniques; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Neurons, Afferent; Neurotoxins; Pancreas; Perfusion; Random Allocation; Rats; Rats, Zucker

The emetic (retching and vomiting) reflex is an important component of the body's defence system against accidentally ingested toxins and emesis is also a common symptom of disease and a side-effect of a number of pharmacological therapies. The development of the reflex has been the subject of few systematic studies. The aim of this study was to characterise the development of the emetic reflex in Suncus murinus (the house musk shrew) using emetic stimuli acting via three different afferent pathways: motion via the vestibular system, pyrogallol via abdominal vagal afferents and resiniferatoxin (a capsaicin analog) via the brainstem. The emetic reflex was not present to any stimulus prior to postnatal day 10 but the onset of the response to motion lagged behind that to the other stimuli in not being present until postnatal day 15. Body weight was not a determinant of the presence of the reflex. It is proposed that the delayed presence of the emetic reflex in Suncus makes it an ideal species in which to investigate factors regulating its development.

Topics: Age Factors; Animals; Body Weight; Diterpenes; Female; Male; Motion Sickness; Neurotoxins; Pyrogallol; Reflex; Shrews; Solitary Nucleus; Substance P; Vagus Nerve; Vestibule, Labyrinth; Vomiting