Prostaglandin E2 and I2 facilitate noxious heat-induced spike discharge but not iCGRP release from rat cutaneous nociceptors

The bradykinin-induced sensitization of cutaneous nociceptors to heat was previously shown to be abolished by cyclooxygenase blockade suggesting that endogenous prostaglandins exerted a heat-sensitizing action. The present study aimed at investigating the effects of exogenous prostaglandin E-2 (PGE(2)) and I-2 (PGI(2)) on noxious heat-evoked responses of rat cutaneous nociceptors. As neuropeptides including calcitonin gene-related peptide (CGRP) can be released from the peptidergic subset of heat-sensitive nociceptors, both the spike-generating (afferent) and CGRP-releasing (efferent) responses to heat stimulation were assessed by recording action potentials from single cutaneous C-fibers, and measuring immunoreactive CGRP (iCGRP) release from isolated skin flaps, respectively. A combination of PGE(2) and PGI(2) (100 mu M for both) unlike 10 mu M PGE(2) or PGI(2) increased the number of spikes discharged during a noxious heat stimulus whereas the heat threshold remained unchanged. In contrast, 100 mu M PGE(2) plus PGI(2) failed to increase the iCGRP release induced by noxious heat (47 degrees C) from the isolated rat skin. PGE(2) (100 mu M), however, augmented the iCGRP-releasing effect of protons (pH 5.7). The adenylyl cyclase activator forskolin and the protein kinase C activator phorbol ester (PMA, 10 mu M for both) facilitated heat-induced iCGRP release whereas increasing the intracellular Ca2+ concentration by 10 mu M ionomycin produced a desensitization of the response. In conclusion, PGE(2) plus PGI(2) can sensitize the afferent function of nociceptors in the rat skin, by increasing heat-induced spike discharge, but not the heat-induced efferent response i.e. iCGRP release. This discrepancy might reflect the differences between mechanisms of Na+ channel-dependent spike generation and Ca2+-dependent neuropeptide release. (C) 2007 Elsevier Inc. All rights reserved.