TRPV1 In Dorsal Root Ganglion Research Articles

Lactobacillus plantarum AR495 improves stress-induced irritable bowel syndrome in rats by targeting gut microbiota and Mast cell-PAR2-TRPV1 signaling pathway

Probiotics have great potential in regulating intestinal pain. In this study, the effects of Lactobacillus plantarum AR495 on the visceral sensitivity and gut microbiota of irritable bowel syndrome (IBS) rats were studied. The results showed that tryptase released after mast cell activation and degranulation plays a key role in visceral pain, and L. plantarum AR495 reduced the stimulation of colonic mast cells and the expression of protease-activated receptor 2 (PAR2) and TRPV1 in dorsal root ganglia. Research further showed that supplementation with L. plantarum AR495 increased the level of short-chain fatty acids (SCFAs) and enhanced the barrier function of the colon. In addition, the microbiota analysis of the colon indicated that L. plantarum AR495 promoted the proliferation of Bifidobacterium and inhibited the proliferation of Lachnospiraceae, which alleviated the imbalance of the intestinal microbiota caused by IBS to a certain extent. In total, L. plantarum AR495 might reduce visceral sensitivity through the Mast cell-PAR2-TRPV1 signaling pathway by maintaining the homeostasis of the intestinal barrier.

330 The aryl hydrocarbon receptor contributes to histamine-evoked itch with the involvement of TRPV1 in dorsal root ganglia

330 The aryl hydrocarbon receptor contributes to histamine-evoked itch with the involvement of TRPV1 in dorsal root ganglia

Angelica dahurica Extracts Attenuate CFA-Induced Inflammatory Pain via TRPV1 in Mice.

Angelica dahurica, belonging to the family Apiaceae, is a well-known herbal medicine. The roots of Angelica dahurica are commonly used for the treatment of headache, toothache, abscess, furunculosis, and acne. However, little is known about their analgesic molecular mechanism underlying pain relief. In this study, we used behavioral tests to assess the analgesic effect of the ADE (Angelica dahurica extracts) on CFA (complete Freund's adjuvant)-induced inflammatory pain mice models. TRPV1 (Transient Receptor Potential Cation Channel Subfamily V Member 1) protein activity in dorsal root ganglion (DRG) was assessed with a calcium imaging assay. TRPV1 expression was detected with western blot and immunohistochemistry. Then, we examined the constituents of ADE using combined ultra-performance liquid chromatography-quadrupole time-of-light mass spectrometry (UPLC/Q−TOF−MS). Our results showed that ADE effectively attenuated mechanical and thermal hypersensitivities in CFA-induced inflammatory pain model in mice. ADE also significantly reduced the activity and the protein expression of TRPV1 in DRG from CFA mice. Therefore, ADE might be an attractive and suitable analgesic agent for the management of chronic inflammatory pain.

Activation of GPR18 by Resolvin D2 Relieves Pain and Improves Bladder Function in Cyclophosphamide-Induced Cystitis Through Inhibiting TRPV1.

PurposeHyperalgesia and bladder overactivity are two main symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS). Cannabinoid receptors participate in the modulation of pain and bladder function. GPR18, a member of the cannabinoid receptor family, also participates in the regulation of pain and bladder function, but its underlying mechanisms are unknown. In this work, we sought to study the role of GPR18 in IC/BPS.MethodsA rat model of IC/BPS was established with cyclophosphamide (CYP). Paw withdrawal threshold (PWT) measurement and cystometry were used to evaluate pain and bladder function, respectively. RT-PCR, Western blotting and immunofluorescence were used to assess the expression and distribution of GPR18. The role of GPR18 in pain and bladder function was studied by intrathecal injection of resolvin D2 (RvD2, a GPR18 agonist) and O-1918 (a GPR18 antagonist). Calcium imaging was used to study the relationship between GPR18 and TRPV1.ResultsA rat model of IC/BPS, which exhibited a decreased PWT and micturition interval, was successfully established with CYP. The mRNA and protein expression of GPR18 was reduced in the bladder and dorsal root ganglia (DRG) in rats with CYP-induced cystitis. Intrathecal injection of RvD2 increased the PWT and micturition interval. However, O-1918 blocked the therapeutic effect of RvD2. GPR18 was present in bladder afferent nerves and colocalized with TRPV1 in DRG, and RvD2 decreased capsaicin-induced calcium influx in DRG.ConclusionActivation of GPR18 by RvD2 alleviated hyperalgesia and improved bladder function, possibly by inhibiting TRPV1 in rats with CYP-induced cystitis.

Sensory Neuron Sensitization By Pkc-induced Trpv1 Phosphorylation In Type 2 Diabetic Rats

Skeletal muscle reflex-induced increases in blood pressure are exaggerated during exercise in type 2 diabetes mellitus (T2DM). We previously demonstrated that skeletal muscle afferent discharge in response to capsaicin, a transient receptor potential cation channel subfamily V member 1 (TRPV1) agonist, is heightened in T2DM likely contributing to the potentiated pressor response. However, the underlying mechanisms remain unclear. Evidence suggests that the high glucose levels in T2DM sensitize sensory neurons through the receptor for advanced glycation end products (RAGE)/protein kinase C (PKC) pathway in dorsal root ganglia (DRG). Moreover, early-stage diabetes associated with TRPV1 overactivity is mediated through PKC. Therefore, it was hypothesized that the augmentation in muscle afferent discharge in T2DM previously reported is due to the phosphorylation of TRPV1 via an overactive RAGE/PKC pathway. PURPOSE: To investigate 1) the impact of T2DM on plasma levels of advanced glycation end products (AGE) and high-mobility group box-protein 1 (HMGB-1), both RAGE ligands, and 2) the impact of T2DM on the RAGE/PKC pathway including the phosphorylation of TRPV1 in DRG subserving skeletal muscle afferents. METHODS: For 14-16 weeks, Sprague-Dawley rats were given either a normal diet (control) or a high fat diet in combination with a low dose (35 mg/kg) of streptozotocin (T2DM). Plasma insulin, HMGB1 and AGE were determined using ELISA. RAGE, phosphorylated PKC and TRPV1 protein levels were quantified in DRG by western blotting. RESULTS: After overnight fasting, T2DM rats exhibited hyperglycemia (95±6 vs. 156±18 mg/dL, P<0.05) and hyperinsulinemia (1.6±0.2 vs. 4.1±0.4 ng/mL, P<0.05). HMGB1, AGE and RAGE did not differ between groups. Phosphorylated PKC (1.0±0.1 vs. 1.2±0.2 arb unit, P=0.08) and TRPV1 (1.0±0.3 vs. 1.3±0.4 arb unit, P=0.08) levels in DRG tended to be greater in T2DM than control. CONCLUSIONS: These findings suggest that phosphorylated TRPV1 may be increased by PKC overactivity in DRG of T2DM but acts independently of RAGE. Importantly, these changes may mediate the sensitization of skeletal muscle afferents facilitating the exaggerated pressor response to exercise characteristic of T2DM. Supported by Lawson & Rogers Lacy Research Fund and SHP Interdisciplinary Research Grant Program.

Baicalin prevents the up-regulation of TRPV1 in dorsal root ganglion and attenuates chronic neuropathic pain.

BackgroundNeuropathic pain is a major public health problem because it has a considerable impact on life quality of patients. TRP channels from dorsal root ganglion (DRG) play a crucial role in facilitating pain transmission at peripheral and spinal sites. Baicalin has neuroprotective effects and improves the pathological and behavioural outcomes of various types of nerve injury. The present study aims to examine the analgesic effects of baicalin on chronic neuropathic pain.MethodsNeuropathic pain animal model was created by chronic constriction injury of the sciatic nerve (CCI). Behavioural tests were performed by von Frey and hot plate tests. mRNA and protein expression levels were examined by quantitative RT‐PCR and western blot.ResultsConsecutive intraperitoneal administration of baicalin for 16 days reduced the mechanical and thermal nociceptive responses induced by CCI surgery in a dose‐dependent manner. The mRNA expression levels of Trpv1 and Trpa1 were significantly increased in the DRG of CCI rats. Moreover baicalin administration reversed TRPV1 expression and phosphorylation of ERK in DRG neurons after peripheral nerve injury.ConclusionsOur results suggested that baicalin may ameliorate neuropathic pain by suppressing TRPV1 up‐regulation and ERK phosphorylation in DRG of neuropathic pain rats. Baicalin has a significant analgesic effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

Systematic Administration of B Vitamins Alleviates Diabetic Pain and Inhibits Associated Expression of P2X3 and TRPV1 in Dorsal Root Ganglion Neurons and Proinflammatory Cytokines in Spinal Cord in Rats.

Background Treatment of diabetic neuropathic pain (DNP) continues to be a major challenge, and underlying mechanisms of DNP remain elusive. We investigated treatment effects of B vitamins on DPN- and DNP-associated alterations of neurochemical signaling in the nociceptive dorsal root ganglion (DRG) neurons and the spinal cord in rats. Methods DNP was produced in male, adult, Sprague Dawley rats by single i.p. streptozotocin (STZ). Western blot analysis and immunohistochemistry were used to analyze protein expressions in DRG and ELISA to measure the proinflammatory cytokines in the spinal cord. Behaviorally expressed DNP was determined by measuring the sensitivity of hindpaw skin to mechanical and thermal stimulation. Results There were 87.5% (77/88) rats which developed high blood glucose within 1-2 weeks following STZ injection. Of which, 70.13% (n = 54/77) animals exhibited DNP manifested as mechanical allodynia and/or thermal hyperalgesia. Intraperitoneal administration of vitamins B1/B6/B12 (100/100/2 mg/kg, one or multiple doses) significantly attenuated DNP without affecting the blood glucose. Expressions of P2X3 and TRPV1 in CGRP-positive and IB4-positive DRG neurons as well as the interleukin-1β, tumor necrosis factor-α, and nerve growth factor in the lumbar spinal cord were greatly increased in DNP rats. Such DNP-associated neurochemical alterations were also greatly suppressed by the B-vitamin treatment. Conclusions B-vitamin treatment can greatly suppress chronic DNP and DNP-associated increased activities of P2X3 and TRPV1 in DRG and the spinal proinflammatory cytokines, which may contribute to the pathogenesis of DNP. Systematic administration of B vitamins can be a strategy for DNP management in clinic.

Transcription factor Sp4 is required for hyperalgesic state persistence.

Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist—capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.

Overexpression of TRPV1 after periphery nerve injury attenuates nerve regeneration in rats

Objective: To observe the effect of the expressive or functional blockage of TRPV1 on nerve regeneration after sciatic trans-section injury. Methods: AMG-517, a kind of TRPV1 inhibitor, was injected into the surrounding area of the ipsilateral lumbar dorsal root ganglia while unilateral sciatic nerve was transected. A total of 24 healthy male Sprague-Dawley rats were divided into 4 groups: control group, injury only group, injury+ AMG-517 150 μg/kg group, injury+ AMG-517 300 μg/kg group. The injury only group was injected the same volume of medium. The release of CGRP from dorsal-horn of spinal cord, the number of axons at proximal stem of sciatic nerve after transection, and the expression of TRPV1 in dorsal root ganglion were detected using the methods of ELISA, Western blot and semi-thin section (1 μm)- toluidine blue staining 2 weeks after injury. Results: The release of CGRP in lumbar spinal dorsal horn was obviously decreased after AMG-517 treatment, which was the evidence of TRPV1 functional inhibition. CGRP in the control group was 0.15 ng/g, the injury only group 0.17 ng/g, AMG-517 150 μg/kg group 0.09 ng/g, and AMG-517 300 μg/kg group 0.11 ng/g(P<0.01). The number of axons which were myelinated or unmyelinated increased after the TRPV1 was inhibited by AMG-517(P<0.01). In addition, the injection of AMG-517 into surrounding dorsal root ganglion decreased the expression of TRPV1 in dorsal root ganglion(P<0.01). Conclusions: Over expression or activation of TRPV1 after periphery nerve injury has negative effect on nerve regeneration in fact; Inhibiting the over-expression or over-activation of TRPV1 after nerve injury facilitates axonal regeneration and nerve repair.

MOK, a pharmacopuncture medicine, regulates thyroid dysfunction in L-thyroxin-induced hyperthyroidism in rats through the regulation of oxidation and the TRPV1 ion channel

BackgroundIn this study, we evaluated the therapeutic effect of MOK, a pharmacopuncture medicine, on thyroid dysfunction in L-thyroxin (LT4)-induced hyperthyroidism rats.MethodsThe experimental hyperthyroidism model was prepared by the intraperitoneal injection of LT4 (0.5 mg/kg) once daily for 2 weeks in SD rats. MOK extract was injected at doses of 0.3 or 3 mg/kg on acupuncture points in the thyroid glands of LT4-induced hypothyroidism rats once a day for 2 weeks. The body temperature, body weight, and food/water intake were measured once a week for 2 weeks. The levels of thyroid hormones, total cholesterol, LDL-cholesterol, GOT, and GPT were measured in the sera of rats using ELISA and an automatic blood analyzer. The histological changes of thyroid tissues were observed by H&E staining. The expression of thermo-regulating protein, TRPV1 was determined by western blot in dorsal root ganglion (DRG) and brain tissues. We also measured the contents of GSH in the liver and antioxidant enzymes, SOD, and catalase in the liver, heart, and brain tissues by enzyme-based assay and Western blot, respectively.ResultsThe acupuncture of MOK extract on the thyroid gland of LT4-induced hyperthyroidism rats significantly decreased the body temperature, and did not change body weight and food and water intakes. MOK acupuncture significantly increased the level of TSH, and decreased the levels of T3 and T4 in hyperthyroidism rats. The expression of TRPV1 was inhibited in both DRG and brain tissues after MOK acupuncture, and the levels of GOT, GPT, total cholesterol, and LDL-cholesterol were also decreased. MOK acupuncture also inhibited the pathological feature with follicular lining epithelial thicknesses and increased follicular colloid depositions in the thyroid glands of hypothyroidism. MOK acupuncture significantly increased hepatic GSH levels and decreased the expression of SOD and catalase in the liver, heart, and brain tissues of hyperthyroidism rats.ConclusionsThese results suggest that the pharmacopuncture with MOK extract in hyperthyroidism can improve the pathophysiological changes through regulating the body temperature, thyroid hormones imbalance, lipid accumulation, and oxidation. This anti-hyperthyroidism effect of MOK pharmacopuncture is thought to be related to the control of thermo-regulating protein TRPV1 in DRG and brain.

Abstract PR062

Background & Objectives: Nerve growth factor (NGF) induced-transient receptor potential vanilloid type 1 (TRPV1) sensitization augments sympathetic nerve response, which may be detrimental to the ischemic myocardium[1]. We have previously demonstrated that intrathecal morphine preconditioning (ITMP) could reduce myocardial ischemia-reperfusion (I/R) injury [2], while the mechanisms need to be elucidated. This study was designed to investigate the effects of ITMP on spinal NGF-TRPV1 sensitization following myocardial I/R injury and the involvement of μ-opioid receptor. Materials & Methods: All rats were subjected to 30 min ischemia followed by 120 min reperfusion, except the rats in SHAM group. ITMP was produced by three cycles of 5 min intrathecal injection of morphine and 5 min intermission before myocardial ischemia. The μ-opioid receptor (MOR) antagonist CTOP was intrathecally injected 10 min prior to ITMP. The severity of arrhythmia was scored and myocardial infarct size (IS) was measured as the percentage of area at risk (IS/AAR). The co-expression of TRPV1 and MOR in dorsal root ganglion (DRG) was detected by double immunofluorescence assay. The protein levels of NGF and TRPV1 in DRG and spinal cord were detected by western blot and immunohistochemistry methods, respectively. Results: The myocardial infarct size and the incidence of arrhythmia induced by myocardial I/R injury were significantly reduced by IPC and ITMP. However, the cardioprotective effects of ITMP were abolished by CTOP. According to the immunofluorescence results, TRPV1 and MOR were co-expressed in rat DRG neurons, and their expression were obviously elevated after myocardial I/R injury. Both IPC and ITMP markedly inhibited the expression of TRPV1 in DRG neurons while had little effects on the expression of MOR. Moreover, the rise of NGF level in rat DRG as well as the expressions of NGF and TRPV1 in spinal dorsal horn induced by myocardial I/R injury were suppressed by IPC and ITMP. Nevertheless, the effects of ITMP on the expressions of NGF and TRPV1 were also blocked by CTOP.Conclusion: ITMP may exert cardioprotection by inhibiting the expressions of NGF and TRPV1 in DRG and spinal cord via activation of the spinal μ-opioid receptor, and thus prevent NGF-induced TRPV1 sensitization. This work was supported by the National Natural Science Foundation of China (81471145)

Electroacupuncture Attenuates Visceral Pain and Reverses Upregulation of TRPV1 Expression in Adult Rats with Neonatal Maternal Deprivation

Irritable bowel syndrome (IBS) is characterized by chronic visceral hypersensitivity that companied by altered bowel movement. However, the treatment options are very limited. The aim of this study was to investigate effects of electroacupuncture (EA) on visceral hypersensitivity in a rat model of IBS and to explore the underlying mechanisms of EA effects. Visceral hypersensitivity was established by neonatal maternal deprivation (NMD) in male rats on postnatal days 2 - 15. Behavioral experiments were conducted at the age of 7 weeks. Treatment with EA at Zusanli (stomach-36, ST-36) significantly reduced abdominal withdrawal reflex (AWR) scores in NMD rats but not in age-matched healthy control rats. In addition, EA treatment hyperpolarized resting membrane potentials, increased the rheobase and reduced the numbers of action potentials evoked by 2 and 3 times rheobase current stimulation of dorsal root ganglion (DRG) neurons innervating the colon. NMD markedly enhanced expression of TRPV1 in colon related DRGs while EA treatment drastically suppressed the expression of TRPV1 in DRGs of NMD rats. These data suggest that EA treatment produced an analgesic effect, which might be mediated at least in a part by suppression of TRPV1 expression and by inhibition of neuronal excitability of primary sensory neurons in rats with chronic visceral pain.

Bortezomib treatment produces nocifensive behavior and changes in the expression of TRPV1, CGRP, and substance P in the rat DRG, spinal cord, and sciatic nerve.

To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN), we examined the effects of a single-dose intravenous administration of bortezomib and a well-established “chronic” schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP) were studied in L4-L5 dorsal root ganglia (DRGs), spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.

Functional expression of TRPV1 and TRPA1 in rat vestibular ganglia

Both TRPV1 and TRPA1 are non-selective cation channels. They are co-expressed, and interact in sensory neurons such as dorsal root ganglia (DRG) and trigeminal ganglia (TG), and are involved in nociception, being activated by nociceptive stimuli. Immunohistological localization of TRPV1 in vestibular ganglion (VG) neurons has been reported. Although TRPA1 is co-expressed with TRPV1 in DRG and TG neurons, it is unclear whether TRPA1 channels are expressed in VG neurons. Moreover, it is unknown whether TRPV1 and TRPA1 channels are functional in VG neurons. We investigated the expression of TRPV1 and TRPA1 in rat VG neurons by RT-PCR, in situ hybridization, immunohistochemistry, and Ca2+ imaging experiments. Both TRPV1 and TRPA1 RT-PCR products were amplified from the mRNA of rat VG neurons. In situ hybridization experiments showed TRPV1 and TRPA1 mRNA expression in the majority of VG neurons. Immunohistochemistry experiments confirmed TRPV1 protein expression. In Ca2+ imaging experiments, capsaicin, a TRPV1 agonist, induced a significant increase in intracellular calcium ion concentration ([Ca2+]i) in rat primary cultured VG neurons, which was almost completely blocked by capsazepine, a TRPV1-specific antagonist. Cinnamaldehyde, a TRPA1 agonist, also caused an increase in [Ca2+]i, which was completely inhibited by HC030031, a TRPA1-specific antagonist. Moreover, in some VG neurons, a [Ca2+]i increase was evoked by both capsaicin and cinnamaldehyde in the same neuron. In summary, our histological and physiological studies reveal that TRPV1 and TRPA1 are expressed in VG neurons. It is suggested that TRPV1 and TRPA1 in VG neurons might participate in vestibular function and/or dysfunction such as vertigo.

Effect of Inhibited Rab11-FIP3 Expression on Membrane Trafficking of TRPV1 in Dorsal Root Ganglion of Rat

Not much is known about the membrane trafficking of TRPV1, a key player in pain transduction. Rab11-FIP3, which plays a role in various intracellular transportation pathways, has been reported to interact with TRPV1. In this study, in order to examine the role of Rab11-FIP3 in the membrane trafficking of TRPV1, Rab11-FIP3 expression in dorsal root ganglion (DRG) was inhibited using a siRNA technique. Transportation of TRPV1 to membranes was found to decrease when Rab11-FIP3 expression was inhibited, consistent with the results obtained with TRPV1-transfected HEK cells. Taken together, these results indicate that Rab11-FIP3 plays a role in the membrane trafficking of TRPV1.

Differential Regulation of 3-Beta-Hydroxysteroid Dehydrogenase and Vanilloid Receptor TRPV1 mRNA in Sensory Neurons by Capsaicin and NGF

It was the aim of the present study to investigate by RT-PCR the regulation of the mRNA of the neurosteroid-synthesizing enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) and of the vanilloid receptor TRPV1 in dorsal root ganglia (DRGs) of rats during the process of capsaicin denervation of primary sensory neurons and the following regeneration. The expression of 3β-HSD in DRG was increased 3 days after the capsaicin treatment, and it remained at that level during a 22 day observation period. The expression of TRPV1, a specific marker of capsaicin-sensitive small sensory neurons connected to C- and Aδ-fibers, was markedly reduced 3 days after the capsaicin treatment. It slowly recovered during the 22 days observation period reaching almost control levels on day 22. When the capsaicin-treated rats received 5 intraplantar injections of nerve growth factor (NGF), the prototypical neurotrophin for capsaicin-sensitive neurons, on day 1, 2, 3, 5 and 6, both the 3β-HSD and the TRPV1 mRNA had returned to control levels at the time point 8 days after capsaicin. The present results demonstrate that both 3β-HSD and TRPV1 are markers for neurodegeneration and neuroregeneration in capsaicin-sensitive primary afferent neurons, and that NGF is an effective tool to induce recovery after peripheral nerve injury.

Evidence for the involvement of vanilloid receptor in the antinociception produced by the dialdeydes unsaturated sesquiterpenes polygodial and drimanial in rats

This study investigated whether or not the neonatal treatment of rats with the sesquiterpenes polygodial or drimanial could cause persistent antinociception similar to that induced by capsaicin. Rats were injected subcutaneously 48 h after birth with capsaicin (50 mg/kg), polygodial (150 mg/kg), drimanial (150 mg/kg) or vehicle (1ml/kg). Six to eight weeks later, rats were tested in models of nociception. Treatment of rats with capsaicin, polygodial or drimanial produced significant inhibition of the first phase and, to a lesser extent, the second phase of formalin-induced nociception. A significant reduction in Complete Freund’s Adjuvant and capsaicin-induced hyperalgesia was observed in the animals neonatally treated with capsaicin, polygodial or drimanial compared with vehicle-treated rats. Moreover, both sesquiterpenes caused inhibition of plasma extravasation induced by injection of capsaicin. The neonatal treatment with capsaicin, polygodial or drimanial significantly decreased [ 3H]-resiniferatoxin binding sites in the rat spinal cord, but only capsaicin neonatal treatment significantly reduced the expression of TRPV1 in dorsal root ganglia (DRG) when assessed by Western blot. These results extend our previous findings demonstrating that the neonatal treatment of rats with polygodial or drimanial, similar to that reported for capsaicin, produced persistent antinociception in adult animals associated with TRPV1 down-regulation in the spinal cord, but not TRPV1 expression in DRG.