Effects of Volatile Anestehtics on TRPV1 & Surgical Pain

Acute postoperative pain represents a complex physiological and psychological reaction to tissue injury and visceral distention. Better understanding of the cellular and molecular basis for central and peripheral mechanisms of pain will help in the development of better treatments for all such pain. Various members of the transient receptor potential (TRP) family of ion channels, particularly TRPV1 have been strongly implicated in the thermal and chemical hyperalgesic response to acute tissue injury. Yet afferent sensory neurons expressing this same type of polymodal receptor have been found to be, paradoxically, activated by the same volatile general anesthetics (VGAs) used to render patients unconscious and insensitive to pain. The objectives of this research are to 1) explore the molecular basis for regulation of TRPV1 by volatile general anesthetics, and to 2) test whether or not this modulation manifests with altered pain-like behavior in animals. We hypothesis that 1) VGAs commonly used in surgery today activate and sensitize the TRPV1 channel on peripheral nociceptors which results in sensitization and increased levels and duration of postoperative pain and inflammatory states, and that 2) this action also contributes to the pungency of inhaled volatile anesthetics. The Specific Aims identified to accomplish our proposed objectives and to test our stated hypotheses are: 1) Characterize the effects of VGAs on the TRPV1 ion channel expressed in Xenopus oocytes, and test whether or not such effects correlate with their known pungency, 2) Validate in sensory neurons any effects of VGAs on TRPV1 observed when the channel is expressed in Xenopus oocytes, 3) Using patch-clamp recordings and calcium imaging, explore molecular mechanisms through which VGAs affect TRPV1 receptor function, 4)Test whether sensitization of the receptor to the effects of VGAs occurs by stimulation of protein kinase A and/or C, and 5) Test whether VGAs modify carrageenan-induced thermal hyperalgesia in a mouse model of inflammatory pain.