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.

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The analgesic effects of the rat in response to electroacupuncture (EA) or low-dose morphine (3 mg/kg) show marked individual variations. In the midbrain periaqueductal gray (PAG) of the rat, the content of the neuropeptide cholecystokinin octapeptide (CCK-8) was found to be significantly higher in the low responder (LR) rats as compared to that in the high responders (HR). Since PAG has been shown to be a strategic site for CCK-8 to exert an anti-opioid action, a high CCK content in PAG may account for the low analgesic responsiveness to EA and morphine. In order to block the expression of the gene encoding preproCCK in the brain, antisense CCK expression vector pSV2-CCKAS was microinjected into the lateral cerebral ventricle of the rat, leading to a decrease of the CCK-mRNA as well as the CCK-8 content in rat brain. This effect started 4 days after the intracerebroventricular (i.c.v.) injection of the antisense expression vector, and lasted no more than 1 week. This procedure was shown to be very effective in converting LR rats into HR for EA analgesia and morphine analgesia, and also delayed the development of tolerance elicited by prolonged EA stimulation or repeated morphine administration. The time course of the augmentation of opioid analgesia (4-6 days after the i.c.v. injection of the expression vector) paralleled the decrease of the brain CCK-8 content. The results argue that blocking the CCK gene expression in the brain may tilt the balance between opioid and anti-opioid peptides in favor of the former, thus strengthening the EA analgesia and morphine analgesia, and delaying the development of opioid tolerance.

Low and high frequency electro-acupuncture (EA) stimulation was used in rats that had been lesioned by medial forebrain bundle transection. Behavioral tests showed that both low and high frequency EA stimulation significantly reduced the amphetamine-induced rotation 2 weeks after the lesion but only high frequency EA improved the rotational behavior at 4 weeks. Analysis of the dopamine content in the striatum did not show any significant change after EA. In situ hybridization showed that high frequency EA stimulation up-regulated the glial cell line-derived neurotrophic factor (GDNF) mRNA in both sides of the globus pallidus, while low frequency EA only affected the unlesioned side. It suggests that the retrograde nourishment of GDNF to the dopaminergic neurons and the balanced activity of different nuclei in the basal ganglia circuit after EA may contribute to the behavioral improvement in these rats, which might be the factors that underlie the effectiveness of EA in the treatment of Parkinson's disease.