Orphanin FQ (nociceptin) modulates responses of trigeminal neurons evoked by excitatory amino acids and somatosensory stimuli, and blocks the substance P-induced facilitation of N-methyl- d-aspartate-evoked responses

Abstract

The present investigation details the modulation of medullary dorsal horn neuron responses to excitatory amino acids and peripheral cutaneous stimuli by orphanin FQ (nociceptin), an endogenous ligand for the opioid receptor-like 1 receptor. Effects of orphanin FQ, administered microiontophoretically or given intracerebroventricularly, were tested on the responses of nociceptive-specific, wide dynamic range and low threshold neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized (urethane or pentobarbital) male rats. Microiontophoretic application of orphanin FQ reduced the N-methyl- d-aspartate-evoked responses in 86% (71/82) of neurons, and the (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses in 86% (30/35) of neurons. However, orphanin FQ produced a longer lasting inhibitory effect on the N-methyl- d-aspartate-evoked responses relative to the (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses. The inhibitory effect of orphanin FQ was not modality-specific, responses evoked by noxious as well as non-noxious stimuli were reduced in 22/23 neurons. However, the inhibitory effect was more pronounced on noxious stimulus-evoked responses. Naloxone applied at currents that antagonized the inhibitory effects of selective agonists at μ and κ opioid receptors failed to inhibit the effects of orphanin FQ. Microiontophoretic co-application of substance P with N-methyl- d-aspartate facilitated the N-methyl- d-aspartate-evoked responses in 52% (26/50) of nociceptive neurons. Orphanin FQ blocked or reduced the substance P-induced facilitation by 86±24.4% ( n=14). In order to compare electrophysiological data with previous behavioral observations, effects of orphanin FQ administered intracerebroventricularly were tested on the excitatory amino acid-evoked responses. Orphanin FQ reduced the N-methyl- d-aspartate-evoked responses in 85% (11/13) of neurons whereas the (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses were facilitated in 69% (9/13) of neurons. We suggest that orphanin FQ produces a predominantly inhibitory effect on, (i) noxious stimuli evoked responses, (ii) excitatory amino acid receptor-mediated transmission and, (iii) the substance P-induced facilitation of the N-methyl- d-aspartate-evoked responses. We conclude that orphanin FQ primarily produced an antinociceptive action at the level of the dorsal horn of the medulla.