2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and Morphine-Dependence

We previously demonstrated that intracerebroventricular (i.c.v.) administration of the substance P (SP) aminoterminal fragment SP(1-7) attenuates the expression of morphine withdrawal in the male rat. In this study we have used a synthetic analogue of this peptide, i.e. the SP(1-7) amide showing higher binding potency than the native heptapeptide, in a similar experimental set-up. Thus, Wistar male rats were made tolerant to morphine by daily injections of the opiate during 8 days. Following peptide administration (i.c.v.) and a subsequent naloxone challenge a variety of physical syndromes of withdrawal were recorded. We observed that the SP(1-7) amide potently and dose-dependently reduced several signs of reaction to morphine withdrawal. Interestingly, the effect of the peptide amide was significantly attenuated by the addition of the sigma agonist (+)-SKF-10047. We conclude that the SP(1-7) amide mimics the effect of the native SP fragment and that the mechanisms for its action involve a sigma receptor site.

Topics: Animals; Antipsychotic Agents; Brain; Male; Morphine Dependence; Naloxone; Peptide Fragments; Phenazocine; Rats; Rats, Wistar; Substance P; Substance Withdrawal Syndrome

The effects of phencyclidine (PCP) on locomotor activity were compared to those of the stereoisomers of N-allylnormetazocine (NAN) after acute administration to rats. PCP produced swaying and falling movements, increased sniffing behavior, and enhanced horizontal locomotor activity. d-NAN also induced swaying, falling, sniffing behavior and locomotion, and decreased rearing behavior. l-NAN decreased rearing activity, depressed locomotion, antagonized morphine antinociception and precipitated the morphine-withdrawal syndrome. Sensitization to drug-induced sniffing, rearing and locomotion developed after four daily injections of PCP, d-NAN or l-NAN in rats. Rats which were sensitized to PCP-induced locomotion, sniffing, and rearing were also cross-sensitized to both d-NAN and l-NAN. Animals sensitized to the effects of either d- or l-NAN exhibited cross-sensitization to PCP. There was little evidence that the cross-sensitization between the three agents was stereoselective. These data indicate that the acute effects of PCP are similar to those of d-NAN, but differ from l-NAN, the only agent of the three with opioid antagonist properties. The data further indicate that as sensitization to the motor effects develops during repeated administration of PCP, d-NAN or l-NAN, the differences among the three agents become less apparent.

Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Male; Morphine Dependence; Motor Activity; Narcotic Antagonists; Phenazocine; Phencyclidine; Rats; Rats, Inbred Strains; Stereoisomerism

Our present findings suggest that SKF-10,047, the prototype sigma agonist, has its opioid entity residing with its (-) isomer, while both its (+) and (-) isomers possess psychotogenic properties similar to those produced by PCP. We found that (-)-SKF-10,047 blocks EEG and behavioral effects of morphine in the naive rat, precipitates withdrawal in morphine-dependent rats, produces physical dependence as evidenced by naloxone-induced withdrawal, and displaces [3H]dihydromorphine from brain homogenates. (+)-SKF-10,047 did not produce dependence upon chronic treatment, and it did not displace [3H]dihydromorphine from brain homogenates. Such pharmacodynamic dissociation with SKF-10,047 suggests an association of sigma receptors with psychogenic, but not opioid effects. The latter are most likely mediated by mu or kappa receptors.

Topics: Animals; Binding, Competitive; Brain; Dihydromorphine; Electroencephalography; Female; Hallucinogens; Humans; Morphine; Morphine Dependence; Phenazocine; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Stereoisomerism