capsazepine and Peripheral-Nervous-System-Diseases

Vanilloid receptor type 1 (VR1) (TRPV1) is a ligand-gated ion channel expressed on sensory nerves that responds to noxious heat, protons, and chemical stimuli such as capsaicin. Herein, we have examined the activity of the VR1 antagonist capsazepine in models of inflammatory and neuropathic pain in the rat, mouse, and guinea pig. In naïve animals, subcutaneous administration of capsazepine (10-100 mg/kg s.c.) did not affect withdrawal thresholds to noxious thermal or mechanical stimuli. However, pretreatment with capsazepine prevented the development of mechanical hyperalgesia induced by intraplantar injection of capsaicin, with a similar potency in all three species. Capsazepine (up to 100 mg/kg s.c.) did not affect mechanical hyperalgesia in the Freund's complete adjuvant (FCA)-inflamed hind paw of the rat or mouse. Strikingly, capsazepine (3-30 mg/kg s.c.) produced up to 44% reversal of FCA-induced mechanical hyperalgesia in the guinea pig. Capsazepine also produced significant reversal of carageenan-induced thermal hyperalgesia in the guinea pig at 30 mg/kg s.c., but was ineffective in the rat. Similarly, in the partial sciatic nerve ligation model of neuropathic pain, capsazepine was surprisingly effective in the guinea pig, producing up to 80% reversal of mechanical hyperalgesia (1-30 mg/kg s.c.) but had no effect in the rat or mouse. These data show that VR1 antagonists have antihyperalgesic activity in animal models of chronic inflammatory and neuropathic pain, and illustrate species differences in the in vivo pharmacology of VR1 that correlate with differences in pharmacology previously seen in vitro.

Topics: Algorithms; Animals; Anticonvulsants; Capsaicin; Carbamazepine; Dose-Response Relationship, Drug; Guinea Pigs; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Receptors, Drug; Sciatic Nerve

The epsilon-isozyme of protein kinase C (PKCepsilon) and the vanilloid receptor 1 (VR1) are both expressed in dorsal root ganglion (DRG) neurons and are reported to be predominantly and specifically involved in nociceptive function. Using phosphospecific antibody against the C-terminal hydrophobic site Ser729 of PKCepsilon as a marker of enzyme activation, the state-dependent activation of PKCepsilon, as well as the expression of VR1 in rat DRG neurons, was evaluated in different experimental pain models in vivo. Quantitative analysis showed that phosphorylation of PKCepsilon in DRG neurons was significantly up-regulated after carrageen- and Complete Freund's Adjuvant-induced inflammation, while it was markedly down-regulated after chronic constriction injury. A double-labeling study showed that phosphorylation of PKCepsilon was expressed predominantly in VR1 immunoreactivity positive small diameter DRG neurons mediating the nociceptive information from peripheral tissue to spinal cord. The VR1 protein expression showed no significant changes after either inflammation or chronic constriction injury. These data indicate that functional activation of PKCepsilon has a close relationship with the production of inflammatory hyperalgesia and the sensitization of the nociceptors. Inflammatory mediator-induced activation of PKCepsilon and subsequent sensitization of VR1 to noxious stimuli by PKCepsilon may be involved in nociceptor sensitization.

Topics: Animals; Behavior, Animal; Capsaicin; Carrageenan; Disease Models, Animal; Diterpenes; Freund's Adjuvant; Ganglia, Spinal; Hindlimb; Hyperalgesia; Inflammation; Ligation; Male; Neurons; Nociceptors; Pain; Pain Measurement; Peripheral Nervous System Diseases; Phosphorylation; Protein Kinase C; Protein Kinase C-epsilon; Rats; Rats, Sprague-Dawley; Receptors, Drug

VR1 receptors, present on Adelta- and C-fibres and post-synaptic sites within the spinal cord dorsal horn, is an integrator of noxious stimuli. Here, the contribution of spinal VR1 receptors to spinal nociceptive processing in nerve injured (selective spinal nerve ligated SNL) and sham anaesthetised rats was studied. Spinal capsazepine (0.5-30 microM), a competitive VR1 antagonist, reduced noxious evoked responses of spinal neurones to a greater extent in sham operated rats, compared to SNL rats. Significant differences between the effect of spinal capsazepine on the non-potentiated component of the C-fibre evoked response of SNL and sham operated rats are reported (p< 0.01, two-way ANOVA). Our data suggest there is a functional plasticity of the spinal VR1 receptor following nerve injury.

Topics: Action Potentials; Animals; Capsaicin; Denervation; Dose-Response Relationship, Drug; Down-Regulation; Hyperalgesia; Ligation; Nerve Fibers; Nerve Fibers, Myelinated; Neuralgia; Neuronal Plasticity; Nociceptors; Pain Threshold; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Diseases; Physical Stimulation; Posterior Horn Cells; Rats; Receptors, Drug

The local release of pro-inflammatory neuropeptides in the periphery has been associated with the development of neurogenic inflammation. However, there is an increasing number of reports demonstrating tissue-dependent differences regarding the mechanisms engaged by these neuropeptides to initiate and maintain the inflammatory response in the target tissue. Since skin is often involved in tissue injury, the present studies were designed to develop a model for assessing cutaneous peptide secretion as a marker for neurogenic inflammation in skin tissue. Calcitonin gene-related peptide (CGRP), as one of several neuropeptides known to be involved in neurogenic inflammation, was chosen to study capsaicin-induced effects on peripheral neurosecretion. The corial surface of the hairy skin of a rat hindlimb was superfused in vitro, and the basal and capsaicin-evoked peripheral release of immunoreactive CGRP (iCGRP) was measured using a radioimmunoassay. The main objectives of these studies were to characterize the various properties of this release including dose-dependency, exocytosis and receptor-mediation as well as the effects of acute and long-term capsaicin desensitization. Capsaicin significantly and dose-dependently increased the release of iCGRP at concentrations ranging from 3 to 300 microM. Omission of calcium ions or treatment with the competitive capsaicin receptor antagonist capsazepine completely inhibited the capsaicin-induced iCGRP release. Superfusion of the skin with 100 microM capsaicin following a conditioning stimulation with capsaicin at concentrations ranging from 0.3 to 100 microM led to an acute, dose-dependent desensitization of the CGRP response. In addition, chronic desensitization following the neonatal injection of capsaicin completely abolished the acute iCGRP response to capsaicin. The method described here should prove to be a valuable tool for the evaluation of the processes regulating the peripheral, cutaneous release of pro-inflammatory neuropeptides. This strategy, therefore, may lead to a better understanding of the mechanisms involved in the development and maintenance of neurogenic inflammation, particularly in the skin.

Topics: Animals; Basal Metabolism; Biomarkers; Calcitonin Gene-Related Peptide; Capsaicin; Disease Models, Animal; Hindlimb; Male; Nerve Endings; Neuritis; Neuropeptides; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Skin