Transient Receptor Potential Vanilloid 1 Levels Research Articles

The role of calcitonin gene-related peptide on the increase in transient receptor potential vanilloid-1 levels in trigeminal ganglion and trigeminal nucleus caudalis activation of rat

Calcitonin gene-related peptide (CGRP) and transient receptor potential vanilloid-1 (TRPV1) play an important role in the development of pain and migraine pathogenesis. Increase in plasma CGRP levels is associated with delayed migraine-like attacks in migraine patients. Although several lines of evidence have indicated a key role of CGRP in migraine pain, its mechanisms remain unclear. In this study, we aimed to investigate the functional role of CGRP on trigeminal nociceptive pathway by determining the alteration in TRPV1 levels in trigeminal ganglion (TG) and the activation of trigeminal nucleus caudalis (TNC) of rat. Post intravenous injection of CGRP (600ng/kg) at 60min significantly increased the levels of TRPV1, CGRP, phosphorylated protein kinase C and phosphorylated cyclic AMP responsive element-binding protein in TG of rats. The number of small and medium TRPV1 and CGRP positive immunostaining neurons accompanying with co-localization of TRPV1 with CGRP neurons were significantly increased in TG of CGRP-injected rats. The sustained increase in c-Fos expression in TNC neurons was also observed in CGRP-injected rats. These results indicate that CGRP may participate in trigeminal nociceptive system sensitization by induced increase in TRPV1 and CGRP levels in TG neurons and activation of the central neurons in TNC.

Distribution and Expression of Non-Neuronal Transient Receptor Potential (TRPV) Ion Channels in Rosacea

Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.

17β-estradiol modifies TRPV1 mRNA expression in DRG neurons

While it has been demonstrated that women experience greater cancer pain and pain severity than men, the potential role of estrogen in regulating nociception particularly as it relates to tumor pain remains unclear. Current data indicate that estrogens act directly on the nervous system to affect the severity of pain, but the mechanisms underlying this effect are unclear. A major nociceptive mechanism associated with the development of cancer pain is activation of the transient receptor potential vanilloid-1 (TRPV1) channel. TRPV1 is a Ca2+-permeable ionotropic receptor activated by multiple sensory stimuli including heat, acid, and protons. Antagonism of the TRPV1 channel attenuates nociception in a mouse bone cancer pain model. Both estrogen (ER) and TRPV1 receptors are known to be expressed on dorsal root ganglion (DRG) neurons, whose axons transmit pain from the periphery to the spinal cord. This raises the question of whether estrogen can alter TRPV1 receptor expression or function particularly in pain states like cancer pain. The present study was designed to evaluate the effects of estrogen on pain sensitivity and TRPV1 expression in the DRG of male and female C3H mice in a mouse model of bone cancer pain. One goal was to determine whether estrogen modulates nociceptive receptors in the DRG in a manner consistent with its effects on pain sensitivity. This study demonstrated that exposure to 17β-estradiol in gonadectomized males (ORCH+E), but the lack of this same hormone in gonadectomized females (OVX), significantly reduced the mRNA levels of TRPV1 in lumbosacral DRG neurons and this correlated with a reduction in tumor-induced nociception. Our results suggest that modulation of 17β-estradiol causes a down regulation in TRPV1 expression in DRG neurons, which may be associated with a reduction in fibrosarcoma-induced mechanical allodynia in both male female mice.

Cardioprotection by ischemic postconditioning is lost in isolated perfused heart from diabetic rats: Involvement of transient receptor potential vanilloid 1, calcitonin gene-related peptide and substance P

We previously found that the expression of transient receptor potential vanilloid 1 (TRPV1) and contents of calcitonin gene-related peptide (CGRP) and substance P (SP), two main neuropeptides released from TRPV1, were decreased in diabetic hearts. This study aimed to test whether decreased TRPV1, CGRP and SP levels were responsible for the loss of cardioprotection by ischemic postconditioning (IPostC) in isolated perfused heart from streptozotocin-induced diabetic rats. IPostC effectively protected non-diabetic hearts against ischemia/reperfusion injury by improving cardiac function and lowering creatine kinase (CK) and cardiac troponin I (cTnI) release, which could be abolished by inhibiting TRPV1, CGRP receptor or SP receptor. However, IPostC had no effect on cardiac function and the release of CK and cTnI in diabetic hearts regardless of whether TRPV1, CGRP receptor or SP receptor were inhibited. CGRP or SP-induced postconditioning significantly prevented both non-diabetic and diabetic hearts from ischemia/reperfusion injury by improving cardiac function and lowering CK and cTnI release. Additionally, IPostC markedly increased CGRP and SP release in non-diabetic hearts, which could be reversed with TRPV1 inhibition, but not CGRP receptor or SP receptor inhibition. However, IPostC failed to affect CGRP and SP release in diabetic hearts in the presence or absence of TRPV1, CGRP receptor or SP receptor inhibition. These results indicate that the loss of cardioprotection by IPostC during diabetes is partly associated with a failure to increase CGRP and SP release, likely due to decreased TRPV1 expression and CGRP and SP contents in diabetic hearts.

Identification of perineal sensory neurons activated by innocuous heat

C-fiber sensory neurons comprise nociceptors and smaller populations of cells detecting innocuous thermal and light tactile stimuli. Markers identify subpopulations of these cells, aiding our understanding of their physiological roles. The transient receptor potential vanilloid 1 (TRPV1) cation channel is characteristic of polymodal C-fiber nociceptors and is sensitive to noxious heat, irritant vanilloids, and protons. By using immunohistochemistry, in situ hybridization, and retrograde tracing, we anatomically characterize a small subpopulation of C-fiber cells that express high levels of TRPV1 (HE TRPV1 cells). These cells do not express molecular markers normally associated with C-fiber nociceptors. Furthermore, they express a unique complement of neurotrophic factor receptors, namely, the trkC receptor for neurotrophin 3, as well as receptors for neurturin and glial cell line-derived neurotrophic factor. HE TRPV1 cells are distributed in sensory ganglia throughout the neuraxis, with higher numbers noted in the sixth lumbar ganglion. In this ganglion and others of the lumbar and sacral regions, 75% or more of such HE TRPV1 cells express estrogen receptor alpha, suggestive of their regulation by estrogen and a role in afferent sensation related to reproduction. Afferents from these cells provide innervation to the hairy skin of the perineal region and can be activated by thermal stimuli from 38 degrees C, with a maximal response at 42 degrees C, as indicated by induction of extracellular signal-regulated kinase phosphorylation. We hypothesize that apart from participating in normal thermal sensation relevant to thermoregulation and reproductive functions, HE TRPV1 cells may mediate burning pain in chronic pain syndromes with perineal localization.

TRPV1: Contribution to Retinal Ganglion Cell Apoptosis and Increased Intracellular Ca2+with Exposure to Hydrostatic Pressure

Elevated hydrostatic pressure induces retinal ganglion cell (RGC) apoptosis in culture. The authors investigated whether the transient receptor potential vanilloid 1 (TRPV1) channel, which contributes to pressure sensing and Ca(2+)-dependent cell death in other systems, also contributes to pressure-induced RGC death and whether this contribution involves Ca(2+). trpv1 mRNA expression in RGCs was probed with the use of PCR and TRPV1 protein localization through immunocytochemistry. Subunit-specific antagonism (iodo-resiniferatoxin) and agonism (capsaicin) were used to probe how TRPV1 activation affects the survival of isolated RGCs at ambient and elevated hydrostatic pressure (+70 mm Hg). Finally, for RGCs under pressure, the authors tested whether EGTA chelation of Ca(2+) improves survival and whether, with the Ca(2+) dye Fluo-4 AM, TRPV1 contributes to increased intracellular Ca(2+). RGCs express trpv1 mRNA, with robust TRPV1 protein localization to the cell body and axon. For isolated RGCs under pressure, TRPV1 antagonism increased cell density and reduced apoptosis to ambient levels (P <or= 0.05), whereas for RGCs at ambient pressure, TRPV1 agonism reduced density and increased apoptosis to levels for elevated pressure (P <or= 0.01). Chelation of extracellular Ca(2+) reduced RGC apoptosis at elevated pressure by nearly twofold (P <or= 0.01). Exposure to elevated hydrostatic pressure induced a fourfold increase in RGC intracellular Ca(2+) that was reduced by half with TRPV1 antagonism. Finally, in the DBA/2 mouse model of glaucoma, levels of TRPV1 in RGCs increased with elevated IOP. RGC apoptosis induced by elevated hydrostatic pressure arises substantially through TRPV1, likely through the influx of extracellular Ca(2+).

Impaired transient receptor potential vanilloid 1 in streptozotocin-induced diabetic hearts

Little is known about the effect of diabetes mellitus (DM) on transient receptor potential vanilloid 1 (TRPV1) located in cardiac sensory nerves. This study was performed to test the changes of TRPV1 and its main neuropeptides in diabetic hearts. DM was induced by intraperitoneal injection of streptozotocin (STZ) in C57BL/6J mice. The protein and mRNA expression of TRPV1, calcitonin gene-related peptide (CGRP) and substance P (SP) levels in hearts were measured, respectively. Compared with control mice, blood glucose was significantly increased in diabetic mice ( P < 0.05), while the protein and mRNA expression of TRPV1, CGRP and SP levels in hearts were essentially reduced in diabetic mice ( P < 0.05). TRPV1 and its main neuropeptides, CGRP and SP, in hearts were impaired during DM.

The Relief of Postoperative Pain

Targeting peripheral neuropathic pain at its origin may prevent the development of hypersensitivity. Recently we showed this can be mediated by opioid receptors at the injured nerve trunk. Here, we searched for the most relevant peripheral site to block transient receptor potential vanilloid 1 (TRPV1), and investigated analgesic interactions between TRPV1 and opioids in neuropathy. In a chronic constriction injury (CCI) of the sciatic nerve in mice, we assessed the effects of μ-, δ- and κ-opioid receptor agonists and TRPV1 antagonist (SB366791) injected at the CCI site or into the injured nerve-innervated paw on spontaneous paw lifting, heat and mechanical sensitivity. We also examined TRPV1 expression in total membrane and plasma membrane fractions from nerves and paws. We found that opioids and SB366791 co-injected in per se nonanalgesic doses at the CCI site or into the paw diminished heat and mechanical sensitivity. SB366791 alone dose-dependently alleviated heat and mechanical sensitivity. TRPV1 blockade in the paw was more effective than at the CCI site. None of the treatments diminished spontaneous paw lifting. TRPV1 expression analysis suggests that the levels of functional TRPV1 do not critically determine the TRPV1 antagonist-mediated analgesia. Together, the identification of the primary action site in damaged nerves is crucial for effective pain control. Contrary to opioids, the TRPV1 blockade in the injured nerve peripheral terminals, rather than at the nerve trunk, appears promising against heat pain. Opioid/TRPV1 antagonist combinations at both locations partially reduced neuropathy-triggered heat and mechanical pain.