Activation of spinal ORL-1 receptors prevents acute cutaneous neurogenic inflammation: role of nociceptin-induced suppression of primary afferent depolarization.

Neurogenic inflammation is an inflammatory response of peripheral tissue to vasoactive substances released from sensory afferent terminals. It can be triggered via a local axon reflex and by dorsal root reflex (DRR) activity involving the spinal cord. Nociceptin, an endogenous ligand for the opioid receptor-like (ORL-1) G-protein coupled receptor, has been found to inhibit the local axon reflex-mediated neurogenic inflammation by suppressing the release of vasoactive neuropeptides from sensory afferent terminals. The present study was to explore the role of spinal ORL-1 receptors in the modulation of DRR-induced neurogenic inflammation. We first examined the effect of nociceptin on DRR by recording dorsal root potentials (DRPs) and the associated antidromic discharges, evoked by electrical stimulation of an adjacent dorsal root in an in vitro neonatal rat spinal cord preparation. Nociceptin reversibly inhibited the DRP in a concentration-dependent manner (IC50: approximately 45 nM, maximal inhibition: approximately 50%), an effect that was antagonized by the ORL-1 receptor antagonist, J-113397. Neurochemical studies demonstrated that nociceptin (10 microM) also produced an approximately 40% reduction in gamma amino butyric acid (GABA) release evoked by electrical stimulation of neonatal rat spinal cord slices. On the other hand, nociceptin had no effect on exogenous GABA-evoked DRP. These findings suggest that the nociceptin-induced inhibition of the DRP is most likely due to the suppression of GABA release, the principle transmitter mediating DRP, from GABAergic neurons that are pre-synaptic to primary afferent terminals. Finally, in order to explore the physiological significance of such modulation in a fully integrated system, we evaluated the effect of intrathecally administered nociceptin on capsaicin-induced acute cutaneous neurogenic inflammation in rat hind paw, quantified by examining the degree of paw edema in anesthetized rats. The magnitude of capsaicin-induced increase of paw thickness was reduced by approximately 50% from 31+/-1.34% (n=6) to 15+/-1.63% (n=8; P<0.05) by nociceptin (10 micromol). We conclude that spinal ORL-1 receptors can modulate neurogenic inflammation by suppressing the GABAergic neuronal activity in the dorsal horn that is responsible for generating DRRs.