Endovanilloid signaling in pain.
Recent work has addressed the role of vanilloid receptor type 1 (VR1) in pain perception. VR1 activity is regulated both directly and indirectly by endogenous factors. For example, protein kinase C sensitizes human VR1 to mild decreases in pH, which are commonly encountered during inflammation, and renders the endocannabinoid anandamide a more potent 'endovanilloid'. Bradykinin and nerve growth factor release VR1 from the inhibitory control of phosphatidylinositol (4,5)-bisphosphate and anti-VR1 serum ameliorates thermal allodynia and hyperalgesia in diabetic mice. There is strong evidence that not only the sensitivity but also the density of expression of VR1 is enhanced during inflammatory conditions. These observations provide an empirical foundation which could explain the reduced inflammatory hyperalgesia in VR1 knockout mice, and they imply an important role for endovanilloid signaling via VR1 in the development of ongoing pain in humans that occurs in most inflammatory conditions. Conversely, downregulation of VR1 expression and/or activity is a promising therapeutic strategy for novel analgesic drugs.
Di Marzo
Vincenzo
V
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Edificio 70, 80078 Pozzuoli, Napoli, Italy. vdimarzo@icmib.na.cnr.it
Blumberg
Peter M
PM
Szallasi
Arpad
A
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001920:Bradykinin / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D063388:Endocannabinoids; D006801:Humans; D006930:Hyperalgesia; D007249:Inflammation / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D010146:Pain / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D011493:Protein Kinase C / Q000378:metabolism; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug; D020932:Nerve Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D001920:Bradykinin; C078814:anandamide