n-methylnaloxone and Morphine-Dependence

The purpose of the present study was to investigate the role of the locus coeruleus in the development of opiate dependence. Two groups of rats each were subjected to either a electrolytic lesion of the locus coeruleus or a sham lesion. All animals were implanted with an intracerebroventricular (i.c.v.) cannula, and made physically dependent by subcutaneous insertion of two 75-mg morphine (base) pellets. Abstinence was precipitated by i.c.v. administration of methylnaloxonium (31-1,000 ng) 72 h after pellet implantation. Methylnaloxonium administered intracerebroventricularly induced a withdrawal syndrome characterized by the appearance of teeth chattering, mastication, rearing, wet dog shakes, jumping, piloerection, hyperactivity, ptosis and eye twitch. Withdrawal observed in the electrolytic lesion groups was less severe than in sham group. The presence of mastication, rearing, piloerection, hyperactivity, ptosis and eye twitch was significantly lower. These results support the hypothesis that the locus coeruleus has an important role in the expression of the physical signs of opiate dependence.

Topics: Animals; Blepharoptosis; Body Weight; Brain Chemistry; Dose-Response Relationship, Drug; Eye Movements; Injections, Intraventricular; Locus Coeruleus; Male; Mastication; Morphine; Morphine Dependence; Motor Activity; Naloxone; Norepinephrine; Piloerection; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Specific brain sites for the opiate abstinence syndrome syndrome have been elusive to delineate, and the classic overt signs of withdrawal such as wet dog shakes, ptosis and teeth chattering appear to be widely represented in the brain. Using a more general motivational test involving a disruption of operant behavior in dependent rats, the brain site most sensitive to the response disruptive effects of intracerebral administration of the opiate antagonist, methylnaloxonium, was the region of the nucleus accumbens, a site also implicated in the acute reinforcing properties of opiates. This disruption of operant responding was hypothesized to reflect the aversive properties of opiate withdrawal. The present study directly tested that hypothesis by exploring whether intercerebral administration of methylnaloxonium produced aversive stimulus effects as measured by the formation of place aversions. Rats implanted intracerebroventricularly or with bilateral cannulae aimed at the medial dorsal thalamus, periaqueductal gray, ventral tegmental area, amygdala or nucleus accumbens were made dependent on morphine by subcutaneous implantation of two 75-mg morphine pellets. The animals were then subjected to place aversion training by pairing of a distinct environment (one of three arms of a three-armed box with distinct texture, markings and smell) with a single injection of methylnaloxonium intracerebroventricularly or intracerebrally. Results showed that at high doses of methylnaloxonium (1000-2000 ng) all sites produced a place aversion. However, lower doses (250-500 ng) produced a significant brain site selectivity with the region of the nucleus accumbens the most sensitive. Observational measurements taken during the postinjection period with the high dose of methylnaloxonium showed that agitation was particularly observed following methylnaloxonium administration into the nucleus accumbens and periaqueductal gray.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amygdala; Animals; Conditioning, Operant; Injections, Intraventricular; Male; Morphine Dependence; Naloxone; Nucleus Accumbens; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome