1 The present study was designed to investigate further the e ects of the newly discovered orphanin FQ (OFQ) ± the endogenous ligand for the orphan opioid receptor (called, e.g., ORL 1 and LC132) ± on pain modulation in the rat. We used the tail-¯ick assay as a nociceptive index. 2 When injected into a cerebral ventricle, OFQ (4 fmol ± 10 nmol) has no e ect on basal tail-¯ick latency by itself at any dose, but dose-dependently antagonizes systemic morphine analgesia (400 fmol ± 50 nmol). 3 Injected intrathecally, OFQ (3 and 10 nmol) displayed an analgesic e ect without producing motor dysfunction, and potentiated morphine analgesia (1 and 10 nmol). 4 The anti-opioid e ect of OFQ in rat brain and the high level of expression of LC132/ORL 1 receptor in the locus coeruleus indicated a possible role of OFQ in the precipitation of opiate withdrawal symptoms. However, no such precipitation was observed by OFQ in morphine-dependent rats.

Our previous work has demonstrated that exogenously administered orphanin FQ (OFQ) antagonizes morphine analgesia and electroacupuncture analgesia (EAA) in the brain and potentiates morphine analgesia and EAA in the spinal cord of the rat. In the present study we evaluated the role of endogenously released OFQ in the development of tolerance to morphine and electroacupuncture (EA) and the analgesia produced by electroacupuncture, by use of the IgG fraction of an anti‐OFQ antibody (OFQ‐Ab) microinjected into the rat central nervous system (CNS). EAA was produced by stimulating rats at a frequency of 100 Hz. Rats were classified as either high responders (HR) or low responders (LR) based on the analgesic effects of EA. LRs could be converted into HRs by the intracerebroventricular (i.c.v.) microinjection of OFQ‐Ab at both 1 : 1 and 1 : 10 dilutions but not 1 : 100. HRs could be changed into LRs by the intrathecal (i.t.) injection of OFQ‐Ab at both 1 : 1 and 1 : 10 dilutions, but not 1 : 100. Acute morphine tolerance was induced in rats by repeated subcutaneous (s.c.) injections of morphine (5 mg kg, every 2 h) for 16 h. When injected i.c.v. the OFQ‐Ab (1 : 1 dilution) had no effect on the development of acute morphine tolerance. Chronic morphine tolerance was produced in rats by repeated injection of morphine (5–60 mg kg, s.c., 3× a day) for 6 days. I.c.v. injection of OFQ‐Ab (1 : 1 dilution) reversed this type of morphine tolerance in rats by 50% (P<0.01). Acute tolerance to the analgesia produced by EA developed after 6 h of continuous (100 Hz, 3mA) stimulation. This tolerance was almost completely reversed by the i.c.v. injection of OFQ‐Ab (1 : 1 dilution) (P<0.05). Chronic tolerance to the analgesic effect of EA was produced by repeatedly administering increasing current (1, 2 and 3 mA, each lasting for 10 min, for a total of 30 min) at a frequency of 100 Hz once a day for 6 days. I.c.v. injection of OFQ‐Ab (1 : 1 dilution) reversed this kind of tolerance by 50% (P<0.01). Together these results suggest that 100 Hz EA may enhance the release of endogenous OFQ in the CNS of the rat, which in turn may act to antagonize EA‐produced analgesia in the brain but potentiate EA produced analgesia in the spinal cord. Therefore, OFQ appears to play an important role in the development of tolerance to the analgesic effects produced by EA. The mechanisms underlying the development of acute morphine tolerance and chronic morphine tolerance appear to be different. Central OFQ may play an important role in the development of tolerance after chronic morphine administration.

Recent studies suggest that the novel opioid peptide orphanin FQ (OFQ) is involved in pain modulation. We found that intracerebroventricular (i.c.v.) administration of OFQ in the rat produced a dose-dependent antagonism of the analgesia induced by 100 Hz electroacupuncture (EA) stimulation as measured in the radiant heat tail-flick assay. Antisense oligonucleotides injected i.c.v. potentiated EA analgesia, presumably by interfering with the expression of the OFQ receptor in brain. These results suggest that endogenous OFQ exerts a tonic antagonistic effect on EA-induced analgesia. No such antagonism was observed when OFQ was injected intrathecally (i.t.). Rather, it appears that spinal OFQ produced a marked analgesic effect and enhanced EA-induced analgesia. These findings are consistent with the experimental results obtained in rats where morphine-induced analgesia is antagonized by i.c.v. OFQ and potentiated by i.t. OFQ.

Nocistatin is a recently characterized neuropeptide derived from the preprohormone containing nociceptin (Orphanin FQ, OFQ). Nocistatin was reported to antagonize OFQ induced allodynia, hyperalgesia and prostaglandin E2-elicited pain responses. The aim of the present study was to determine whether nocistatin, injected intracerebroventricularly (i.c.v.), would reverse the anti-morphine effect of OFQ in rats using the tail-flick latency (TFL) as the nociceptive index. I.c.v. injection of nocistatin at doses of 0.005, 0.05, 0.5, 5, 50, and 500 ng produced no significant changes in the basal TFL, nor did it affect morphine analgesia. However, it significantly reversed the antagonistic effect of OFQ on morphine analgesia when co-injected i.c.v. at doses of 0.05, 0.5, 5, 50 and 500 ng per rat with OFQ. The dose-response curve was bell-shaped and the most effective dose was 0.5 ng. The results suggest that nocistatin can reverse the anti-morphine effect of OFQ in rat brain.