Elsevier

Peptides

Volume 21, Issue 7, July 2000, Pages 969-976
Peptides

Regular paper
Cellular neurophysiological actions of nociceptin/orphanin FQ

https://doi.org/10.1016/S0196-9781(00)00235-7Get rights and content

Abstract

Cellular actions of nociceptin/orphanin FQ (N/OFQ) resemble those of μ-, δ-, and κ-opioids, i.e. activation of inwardly rectifying K+ conductance, inhibition of high-voltage-activated Ca2+ channel currents, and impediment of neurotransmitter release. Differences in ORL1 and μ-receptor distribution lead to: 1) more widespread actions of N/OFQ on periaqueductal gray neurons than opioids and 2) differential effects of N/OFQ and opioids in the brainstem. Also, unlike opioids, N/OFQ inhibits T-type Ca2+ channel current in sensory neurons. Opioids and N/OFQ may modulate glutamate responses in different ways, and certain actions of N/OFQ are potentiated following nerve injury whereas those of μ-opioids are attenuated. Agonists at ORL1 receptors may therefore be of clinical interest in the management of neuropathic pain.

Introduction

Molecular cloning of the μ-, δ-, and κ-opioid receptors led to the discovery of a novel receptor identified as opioid-like receptor 1 (ORL1) [51], [59] whose putative ligand is the heptadecapeptide nociceptin/orphanin FQ (hereafter referred to as N/OFQ). Although N/OFQ appears to have analgesic actions in the spinal cord [32], [34], it may induce hyperalgesia when injected intracerebroventricularly [59]. However, it should also be noted that this initial observation of an hyperalgesic action of N/OFQ [59] has been questioned [34].

Despite this, the cellular actions of N/OFQ resemble those of “classic” analgesic opioid agonists. That is, suppression of Ca2+ channel current (ICa), activation of an inwardly rectifying K+ conductance and suppression of neurotransmitter release. This paper compares details of the neurophysiological actions of N/OFQ with those of “classic” opioids in an attempt to define a cellular basis for reported differences in their behavioral actions.

Section snippets

Actions of nociceptin in cell expression systems

In Xenopus oocytes transfected with the ORL1 receptor and an inwardly rectifying K+ channel comprised of K+ channel subunits Kir3.1 (GIRK1) and Kir3.4, N/OFQ concentration dependently activates an inwardly rectifying K+ current [49]. Although dynorphin A, a κ-opioid receptor agonist, has some affinity for the ORL1 receptor [85], it is an unlikely endogenous ligand [49]. Similar effects of N/OFQ on K+ currents have been obtained from Xenopus oocytes expressing only GIRK1 and the ORL1 receptor

Actions of nociceptin in sensory neurons

Neurons whose cell bodies reside in the dorsal root ganglia (DRG) transmit sensory information from the periphery to the spinal cord. The analgesic actions of “classic” opioid agonists, such as morphine, are thought to involve a reduction in transmitter release from the terminals of these neurons in the spinal cord [38], [79]. This effect likely involves suppression of calcium current (ICa) at presynaptic terminals [35]. Since it is not feasible to study Ca2+ channels in primary afferent

Actions of nociceptin in the dorsal horn of the spinal cord

The analgesic actions of opioids in the spinal cord involve presynaptic mechanisms, such as reduction in transmitter release [26], [28], [38], [40], [79], as well as postsynaptic actions such as activation of an inwardly rectifying K+ conductance [29], [30]. N/OFQ also appears to have a general inhibitory action in the dorsal horn of the spinal cord, which is reminiscent of the actions of μ-, δ-, and κ- opioid agonists.

Repetitive stimulation of afferent nociceptive C-fibers invokes a phenomenon

Actions of nociceptin in the periaqueductal gray

The midbrain periaqueductal gray matter (PAG) comprises the dorsolateral, dorsomedial, lateral, and ventrolateral regions. Neurons in the ventrolateral PAG are of special interest as they project to the rostral ventromedial medulla (RVM) and thence to the dorsal horn of the spinal cord [5], [57]. Opioids are thought to exert an antinociceptive effect by disinhibiting neurons in the ventrolateral PAG that project to the RVM [57]. Although N/OFQ and μ-opioids affect the same set of ionic

Actions of nociceptin in brainstem nuclei

As described above the, PAG has projections to the RVM, a region important for modulating nociceptive transmission. In the RVM, two cell types are thought to be involved in pain modulation and have different responses to opioids [25]. “On-cells” discharge prior to the occurrence of a nociceptive reflex and these are directly inhibited by opioids, whereas “off-cells” terminate firing prior to the occurrence of a nociceptive reflex, and these cells are activated, via disinhibition, by opioids.

Actions of nociceptin in the hippocampus

In dissociated hippocampal CA3 and CA1 neurons, N/OFQ has been reported to inhibit HVA ICa (L-, N-, and P/Q-type channels) [39]. This action of N/OFQ involved a slowing of activation kinetics consistent with a G-protein signaling mechanism. Also, when GTP-γ-S was placed in the recording pipette, N/OFQ produced irreversible suppression of the currents, and incubation with PTX abolished the response to N/OFQ. However, the reported effects of N/OFQ on L-type ICa are controversial, as μ-, δ-, and

Nociceptin in hypothalamic nuclei

In the arcuate nucleus and ventromedial hypothalamus (VMH), nuclei associated with neuroendocrine function, N/OFQ appears to have both pre- and postsynaptic actions. In the arcuate nucleus and VMH N/OFQ activated a Ba2+-sensitive inwardly rectifying K+ conductance and hyperpolarized neurons in the arcuate nucleus and VMH [23], [44], [71]. This K+ conductance in the arcuate nucleus and VMH was similar to the inwardly rectifying K+ conductance activated by N/OFQ in the PAG, dorsal raphe, locus

Summary and conclusions

The cellular electrophysiological actions of N/OFQ thus appear similar to those of μ-, δ-, and κ-opioids. These actions are summarized in Table 1. In almost all central neurons that have been tested, N/OFQ activates an inwardly rectifying K+ conductance in a manner similar to “classic” opioid agonists. It also inhibits Ca2+ channels in dissociated peripheral and central neurons and likely inhibits these same Ca2+ channels at presynaptic terminals in various regions in the CNS. Although these

Acknowledgments

This work was supported by the Medical Research Council of Canada (MRC). Timothy Moran gratefully acknowledges studentship support from the MRC.

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