Unaltered peripheral excitatory actions of nociceptin contrast with enhanced spinal inhibitory effects after carrageenan inflammation: an electrophysiological study in the rat

Abstract

Nociceptin (orphanin FQ) is the endogenous agonist of the opioid receptor-like (ORL-1) receptor. The actions of this peptide have been studied extensively at a number of sites with diverse actions being reported. Here, in a rat model of peripheral inflammation, we examine the effects of nociceptin on the responses of dorsal horn neurones when applied directly to the spinal cord and, in separate studies, into the peripheral receptive fields in the hindpaw of the halothane anaesthetized rat. As changes in the receptor density and expression of the message for nociceptin have been reported after inflammation we have compared these actions to previously reported effects in normal animals. The dose-dependent inhibitory actions of nociceptin on C-fibre evoked responses and input (measures of presumed pre-synaptic excitability) are increased 3-4 h after inflammation whereas its inhibitory effects on post-synaptic mechanisms (wind-up) remain unchanged. These inhibitory effects were partly reversible by high doses of naloxone. This increased potency of nociceptin after inflammation is consistent with an increased receptor density in the superficial spinal cord. In contrast, the peripheral administration of nociceptin produced dose-dependent excitations of dorsal horn neurones and a degree of sensitization to mechanical stimuli. This peripheral action was unchanged after inflammation. These diverse site-dependent actions of nociceptin further emphasize the complexities of this novel opioid system.

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

“…Similarly, EDN at GB30 and GB34 also increased spinal N/OFQ and ORL-1 receptors density, and N/OFQ antagonist blocked the analgesic effects of EDN [203]. According to Carpenter et al the purpose of the added ORL-1 receptors may be to amplify the effects of N/OFQ in the spinal cord [202]. Interestingly, a number of studies have demonstrated that spinal N/OFQ inhibits C-fiber pain signals while preserving Aδ pain [204,205].…”

“…N/OFQ is an opioid related peptide and endogenous agonist of opioid receptor-like receptor (ORL-1). The actions of N/OFQ depend on its location in the body [202]. While supraspinal and peripheral N/OFQ leads to increased nociception, its spinal actions have a powerful antinociceptive effect that mimics opioids [202].…”

“…The actions of N/OFQ depend on its location in the body [202]. While supraspinal and peripheral N/OFQ leads to increased nociception, its spinal actions have a powerful antinociceptive effect that mimics opioids [202]. In as little as 3-hours following the induction of inflammation with carrageenan in a rat model, Carpenter et al noted increased spinal ORL-1 receptor density, which correlated with decreased pain behavior [202].…”

“…While supraspinal and peripheral N/OFQ leads to increased nociception, its spinal actions have a powerful antinociceptive effect that mimics opioids [202]. In as little as 3-hours following the induction of inflammation with carrageenan in a rat model, Carpenter et al noted increased spinal ORL-1 receptor density, which correlated with decreased pain behavior [202]. Similarly, EDN at GB30 and GB34 also increased spinal N/OFQ and ORL-1 receptors density, and N/OFQ antagonist blocked the analgesic effects of EDN [203].…”

“…The fact that N/OFQ and ORL-1 receptor are manufactured in DRG neurons and expressed in the DRG and spinal cord further suggest that the actions of N/OFQ may specifically target presynaptic sensory afferents rather than postsynaptic neurons [206]. As such, N/OFQ is perfectly positioned to inhibit C-fiber pain, thereby preventing and/or blocking central mediated sensitization [202,204]. Previous research has demonstrated that N/OFQ is able to presynaptically block the release of glutamate [207] and substance-P [208] preventing the up regulation of glutamatergic receptors on dorsal horn neurons and the disinhibition of receptive fields.…”