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Vol. 282, Issue 2, 858-865, 1997
The George C. Cotzias Laboratory of Neuro-Oncology, The cloning of a fourth member of the opioid receptor family has led to
the discovery of a new neuropeptide termed orphanin FQ or nociceptin
(OFQ/N). Studies in CD-1 mice confirm the ability of OFQ/N to rapidly
induce hyperalgesia within 15 min which is insensitive to opioid
antagonists. This is followed in the next 30 min by loss of
hyperalgesia and the appearance of analgesia in the tailflick assay
which is readily reversed by opioid antagonists. However, the very poor
affinity of OFQ/N for all the traditional opioid receptors and the
insensitivity of OFQ/N analgesia to antisense oligodeoxynucleotides
active against MOR-1, DOR-1 or KOR-1 sequences that selectively block
mu, delta or kappa1
analgesia, respectively, make it unlikely that OFQ/N analgesia is
mediated through typical opioid receptors. Blockade of the antiopioid
system by haloperidol enhances the analgesic potency of OFQ/N of
more than 100-fold. This effect is pronounced in BALB-C and
Swiss-Webster mice. Although OFQ/N alone has little analgesic activity
in these mice, the blockade of sigma systems with
haloperidol uncovers a robust analgesic response in both strains. Two
shorter OFQ/N fragments, OFQ/N(1-7) and OFQ/N(1-11), also are
analgesic in CD-1 mice and their actions are reversed by the opioid
antagonist diprenorphine despite very poor affinities of both peptides
against [125I]OFQ/N binding and all the opioid
receptors. In antisense studies, a probe targeting the first coding
exon of KOR-3 eliminates OFQ/N hyperalgesia, but not OFQ/N analgesia.
Conversely, antisense probes based on the second and third coding exons
are inactive against OFQ/N hyperalgesia but readily reverse
3 opioid analgesia. These results suggest that
OFQ/N elicits both analgesia and hyperalgesia through pharmacologically
distinct receptors that do not correspond to traditional opioid
receptors.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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