title: Mechanisms involved in potentiation of transient receptor potential vanilloid 1 responses by ethanol.
abstract: The transient receptor potential vanilloid 1 or TRPV1 is a calcium-permeable ion channel that is activated by capsaicin, the active component of hot chilli peppers, and is involved in the development of inflammatory and neuropathic hyperalgesias. Ethanol can sensitise TRPV1-mediated responses, but the pathways contributing to the potentiation of TRPV1 by ethanol have not been clearly defined. Since the mu opioid receptor (MOP) agonist morphine can inhibit TRPV1 responses potentiated by cAMP-dependent protein kinase A (PKA), and ethanol-mediated modulation of other ion channels involves activation of PKA, we aimed to assess the contribution of MOP-sensitive pathways to the potentiation of TRPV1-mediated capsaicin responses by ethanol. Calcium responses elicited by the TRPV1 agonist capsaicin were potentiated by treatment with ethanol, but morphine was not able to inhibit ethanol-sensitised capsaicin responses. Indeed, cAMP-dependent PKA did not appear to contribute to potentiation of TRPV1 responses by ethanol, as the PKA inhibitor Rp-cAMPS did not inhibit ethanol-potentiated capsaicin responses. Similarly, treatment with specific PKC and PI3K inhibitors did not affect capsaicin responses in the presence of ethanol. However, treatment with wortmannin at concentrations reported to cause PIP2 depletion limited the ability of ethanol to sensitise TRPV1-mediated capsaicin responses. Among other plausible mechanisms, such as non-specific inhibition of kinases including mTOR, DNA-PK, MLCK, MAPK and polo-like kinases, this suggests that ethanol may affect the PIP2-TRPV1 interaction. This was confirmed by inhibition of ethanol-potentiation by the PLC inhibitor U73122. The results presented here suggest that morphine may be of limited use in inhibiting nociceptive TRPV1 responses that have been sensitised by exposure to ethanol.
authors.affiliation: The School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wyse
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts-Thomson
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Monteith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cabot
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D004963:Estrenes / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology*; D007668:Kidney / Q000166:cytology; D009020:Morphine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D011869:Radioligand Assay; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000502:physiology*; D014316:Tritium