2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and Substance-Withdrawal-Syndrome

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

Haloperidol, a 'typical' neuroleptic, with affinity for both dopamine (DA) receptors and sigma binding sites, exacerbates morphine withdrawal in guinea-pigs. In this study, the effects of sigma ligands (+)- and (-)-SKF 10,047 (1 and 10 mg/kg s.c.), pentazocine (20 mg/kg s.c.) and DTG (1 and 10 mg/kg s.c.), non-competitive NMDA antagonists ketamine hydrochloride (20 mg/kg s.c.) and MK-801 (0.025, 0.1 and 1 mg/kg s.c.), 'atypical' neuroleptic drugs with (remoxipride 25 mg/kg s.c.) and without (raclopride 10 mg/kg s.c.; clozapine 25 mg/kg s.c.) affinity for sigma sites, and atropine sulphate (20 mg/kg s.c.), were investigated on the opiate withdrawal response induced by naloxone hydrochloride (15 mg/kg s.c.) in guinea-pigs treated 2 h before with a single dose of morphine sulphate (15 mg/kg s.c.). (+)- and (-)-SKF 10,047, pentazocine, ketamine and MK-801, given 0.5 h before naloxone, significantly attenuated the increased locomotor activity and other behaviours associated with morphine withdrawal in guinea-pigs. The selective sigma ligand DTG, and remoxipride had no effect on the withdrawal response but raclopride, clozapine, and atropine exacerbated the response. It is concluded that exacerbation of the morphine withdrawal response by neuroleptics is not related to sigma activity but to other mechanisms. Furthermore NMDA but not sigma mechanisms might play a role in the morphine withdrawal response.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Atropine; Behavior, Animal; Clozapine; Dizocilpine Maleate; Female; Guinea Pigs; Ketamine; Kinetics; Male; Morphine; Motor Activity; Naloxone; Phenazocine; Raclopride; Radioligand Assay; Receptors, sigma; Remoxipride; Salicylamides; Substance Withdrawal Syndrome

Orally-delivered N-allylnormetazocine (NANM) and its isomers were tested for their ability to function as reinforcers by substituting them for phencyclidine (PCP). Two monkeys were trained to self-administer PCP (0.25 mg/ml) and water under concurrent fixed-ratio (FR) 16 schedules during 3-hr sessions. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking devices. When the dextro (+)-isomer of NANM (0.062-1 mg/ml) was substituted for PCP, response rates increased and then decreased in an inverted U-shaped concentration-response function with peak response rates comparable to those maintained by PCP. Drug intake ranged from 2.8 to 25.7 mg/kg across the two monkeys and five concentrations. Water-maintained responding was considerably lower than drug-maintained behavior indicating that NANM was functioning as a reinforcer. As previously reported for PCP, almost all of the (+)-NANM was self-administered during the first half of the session. Substitution of the levo (-)-isomer of NANM resulted in an immediate decline to low response rates that were not distinguishable from those maintained by water. The racemic form (+/-) of NANM was also not self-administered in excess of concurrent water. In the second experiment concurrent PCP- and water-maintained responding were reestablished under FR 8 schedules during three 6.5-hr sessions daily. Food (6 g/pellet) was available under FR 64 and FR 80 schedules during three 1-hr sessions immediately preceding the liquid components. Water was then substituted for PCP for four days and PCP, (+)-, (-)- or (+/-)-NANM were reinstated in subsequent replications of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Macaca mulatta; Male; Phenazocine; Phencyclidine; Self Administration; Stereoisomerism; Substance Withdrawal Syndrome

The repeated administration of phencyclidine (PCP, 72 mg/kg/day) to rats led to physical dependence, as evidenced by a withdrawal syndrome exhibited approx. 24-48 h following suspension of drug. All components of the withdrawal syndrome were suppressed by s.c. injections of PCP (16 mg/kg), (+/-)-N-allylnormetazocine (SKF-10047, 16 mg/kg) and (+)-SKF-10047 (16 mg/kg), but not by injections of saline or (-)-SKF-10047. Moreover, tolerance to the behavioral effects of PCP, as well as cross-tolerance to (+/-)-SKF-10047 and (+)-SKF-10047 were observed. These data indicate that PCP and the sigma opiate SKF-10047 share mechanisms of action, which are mediated by the (+)-isomer of the sigma agonist.

Topics: Animals; Drug Tolerance; Female; Humans; Phenazocine; Phencyclidine; Rats; Receptors, Opioid; Receptors, sigma; Substance Withdrawal Syndrome