ANTINOCICEPTIVE AND MORPHINE MODULATORY ACTIONS OF SPINAL ORPHANIN FQ

Orphanin FQ (nociceptin, OFQ), a heptadecapeptide peptide, has been de signated as an endogenous ligand at the orphan receptor ORL1, which la cks affinity for opioid receptor Ligands. OFQ-like immunoreactivity ha s been localized in spinal cord areas that an involved in the processi ng of nociceptive signals. In this study, the effects of spinally admi nistered OFQ on thermal and mechanical nociceptive stimuli were invest igated following intrathecal (i.t.) injection in unanesthetized rats b earing chronic indwelling catheters in the subarachnoid space. Intrath ecal OFQ produced two distinct acute actions: an opioid-like antinocic eptiwe effect, and antagonism of morphine-induced antinociception, Chr onic administration produces tolerance. Acute actions were as follows. First, injection of OFQ alone in the dose range 10-100 nmol produced sustained antinociceptive effects in the tail-flick (baseline latency 1.5-2 s) and paw-pressure tests. These effects peaked at 45-60 min pos t-injection, were fully reversible, and were observed in absence of di scernable motor impairments. Intrathecal naloxone (5 nmol) significant ly attenuated the antinociceptive effects of OFQ (50 nmol i.t.) in tai l-flick and paw-pressure tests. A 24-h pretreatment with the irreversi ble opioid receptor antagonist, beta-flunatrexamine (2 nmol i.t.), als o attenuated the antinociceptive effects of OFQ (50, 100 nmol i.t.) an d of morphine (7.5 nmol i.t.) in both tests. Low doses (1, 5 nmol) of OFQ, which failed to produce antinociception in the tail-flick test in volving a baseline latency of 1.5-2 s, produced a strong antinocicepti ve response when the baseline latency was increased to 5-6 s. Second, intrathecal OFQ, at doses (0.5, 1.0, and 5.0 nmol) that had no antinoc iceptive activity in the tail-flick (baseline latency 1.5-2 s) and paw -pressure tests, attenuated the antinociceptive effect of morphine (7. 5 nmol i.t.) in these tests. However, a threshold OFQ dose (10 nmol) s ignificantly extended the duration of antinociception induced by morph ine (7.5 nmol i.t.) or deltorphin (20 nmol i.t.). Chronic actions were as follows. In rats that were rendered tolerant to spinal morphine, b y a continuous intrathecal infusion (7.5 nmol/h) of the agonist for 5 days, the OFQ dose-response curves for its antinociceptive effect in t he tail-flick and paw-pressure tests were significantly shifted Co the right. Ln separate experiments, repealed intrathecal injection of OFQ (50 nmol) or morphine (7.5 nmol) produced a significant decline in th eir antinociceptive effects. Thus, intrathecally administered OFQ prod uces both development of tolerance to its antinociceptive actions and cross-tolerance to the action of morphine.