Facilitative interactions between vasoactive intestinal polypeptide and receptor type-selective opioids: implications for sensory afferent regulation of spinal opioid action

Afferent tone is known to influence spinal opioid antinociception but the underlying neurochemical events are not well defined. This study investigates the consequence on cAMP formation of the coincident activation of signal transduction sequelae initiated by an afferent transmitter and opioid using dissociated spinal cord tissue. Afferent transmission was simulated via the addition of vasoactive intestinal polypeptide (VIP), a pelvic visceral afferent transmitter. Individually, mu-, delta-, or kappa-selective opioids (1 muM each) did not alter basal spinal content of cAMP. However, VIP (1 muM) and the delta-opioid selective agonist, [D-Pen(2,5)] enkephalin (DPDPE; 1 muM), in combination, manifest a striking facilitative interaction to augment spinal levels of cAMP. Facilitative interactions between VIP and kappa- or mu-opioids were of a. reduced magnitude or not observed, respectively. Blockade of delta-opioid or VIP receptors using naltrindole or I VIP6-28, respectively antagonized the VIP-DPDPE facilitative interaction, as did pertussis toxin treatment. The VIP-DPDPE facilitative interaction was also eliminated by phospholipase Cbeta inhibition and inositol trisphosphate receptor blockade. This suggests that modulation of Ca2+ trafficking by VIP and delta-opioid agonists is a point of convergence of their respective signal transduction cascades, the concomitant action at which achieves cytosolic Ca concentrations that are now sufficient for the activation of signaling molecules, e.g. Ca /calmodulinstimulated adenylyl cyclase isoforms. These data underscore the plasticity of spinal delta-opioid neurochemical sequelae and their dependence on concomitant afferent transmitter-initiated neurochemical events. (C) 2002 Elsevier Science B.V. All rights reserved.