Circuitry Underlying "Anti-Opioid" Actions of Orphanin FQ in the Rostral
Ventromedial Medulla.
M.M. Heinricher, S. McGaraughty, and D.K. Grandy.
Division of Neurosurgery, Department of Physiology and Pharmacology and the
Vollum Institute, Oregon Health Sciences University, Portland, OR 97201.
APStracts 4:211N, 1997.
ABSTRACT
Several laboratories recently identified a seventeen amino-acid peptide,
termed "nociceptin" or "orphanin FQ," as the endogenous ligand for the LC132
(or "opioid receptor-like1") receptor, a G-protein coupled receptor that does
not bind opioid ligands but which has extensive sequence homology with the
classic opioid receptors. Taken together with the fact that the cellular
effects of OFQ are to a large extent opioid-like, the close relationship
between the LC132 receptor and known opioid receptors raised expectations that
the behavioral effects of this peptide would resemble those of opioids.
However, studies of the role of OFQ in nociception have not provided a unified
view. The aim of the present study was to use a combination of
electrophysiological and pharmacological techniques to characterize the
actions of OFQ in a brain region in which the circuitry mediating the
analgesic actions of opioids has been relatively well characterized, the
rostral ventromedial medulla (RVM).
Single cell recording was combined with opioid administration and local
infusion of OFQ in the RVM of rats lightly anesthetized with barbiturates. The
tail flick reflex was used as a behavioral index of nociceptive
responsiveness. Two classes of physiologically identifiable RVM neurons with
distinct responses to opioids have been characterized. "Off-cells" are
activated, although indirectly, by opioids, and there is strong evidence that
this activation is crucial to opioid antinociception. "On-cells," thought to
enable nociception, are directly inhibited by opioids. Cells of a third class,
"neutral cells," do not respond to opioids, and whether they have any role in
nociceptive modulation remains an open question.
OFQ infused within the RVM profoundly suppressed the firing of all classes of
RVM neurons, blocking opioid-induced activation of off-cells. The
antinociceptive effects of a (-opioid agonist, DAMGO, infused at the same site
were significantly attenuated in these animals by OFQ. Those of systemically
administered morphine, which can produce its antinociceptive effects by acting
at a number of central nervous system sites, were not blocked by RVM OFQ. This
observation is consistent with the fact that the GABAA receptor agonist THIP
also failed to block the effects of systemically administered morphine when
infused into the RVM.
Inasmuch as activation of off-cells can account for the antinociceptive action
of opioids within the RVM, these results demonstrate that, at least within the
medulla, OFQ can exert a functional "anti-opioid" effect by suppressing firing
of this cell class. However, to the extent that antinociceptive and pro-
nociceptive outflows from various brain regions involved in both transmission
and modulation of nociception are active under different conditions, focal
application of OFQ in different regions could potentially produce either
hypoalgesia or hyperalgesia.
Received 13 June 1997; accepted in final form 25 August 1997.
APS Manuscript Number J494-7.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 5 September 1997