n(6)-cyclohexyladenosine and Morphine-Dependence

The isolated guinea pig ileum provides a model in which drug dependence can be induced in normal neurons. The characteristics of opiate dependence in the ileum closely resemble those of dependence in whole animals. Convergent dependence on normorphine, clonidine, and adenosine can be separately induced in the ileum in vitro. Use of selective antagonists indicates that both acetylcholine and substance P participate in the withdrawal response associated with all three of these dependencies. The demonstration that adenosine derivatives suppress opiate withdrawal in the guinea pig ileum and in mice raises the possibility that they might act similarly in man. The point at which the dependencies on normorphine, clonidine, and adenosine converge is probably below their separate recognition sites and is possibly at the level of adenylate cyclase regulation.

Topics: Acetylcholine; Adenosine; Animals; Clonidine; Cyclic AMP; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Morphine; Morphine Dependence; Morphine Derivatives; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Naloxone; Pertussis Vaccine; Scopolamine; Substance P; Substance Withdrawal Syndrome; Substance-Related Disorders; Theophylline; Yohimbine

Effects of different doses of adenosine receptor agonists and antagonists on naloxone-induced jumping and diarrhea in morphine-dependent mice were studied. The adenosine A1 receptor agonists, N6-cyclohexyladenosine (CHA: 0.1, 0.25 and 0.5 mg kg(-1)) and R-isomer of N6-phenylisopropyladenosine (R-PIA: 0.1, 0.3 and 1 mg kg(-1)), decreased jumping and diarrhea induced by naloxone in morphine-dependent mice. The adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 0.3-9 mg kg(-1)), increased jumping but decreased diarrhea. The adenosine A2 receptor agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), decreased jumping and diarrhea. However, the adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX: 0.5 and 1 mg kg(-1)), did not elicit any response in this respect. DPCPX (0.3 and 3 mg kg(-1)), decreased the inhibition of jumping and diarrhea induced by CHA (0.5 mg kg(-1)), while DMPX (0.5 and 1 mg kg(-1)), decreased the inhibition of diarrhea induced by CPCA (0.1 mg kg(-1)). It is concluded that jumping induced by naloxone in morphine-dependent mice may be modified by the adenosine A receptor mechanism(s) and diarrhea induced by the opioid receptor antagonist could be mediated by the adenosine A1 and A2 receptors.

Topics: Adenosine; Analysis of Variance; Animals; Behavior, Animal; Diarrhea; Male; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Substance Withdrawal Syndrome; Theobromine; Xanthines

The stable derivatives of adenosine, 2-chloroadenosine and N6-cyclohexyladenosine, with high affinity for the A1 (Ri) adenosine receptor, suppress the naloxone-precipitated withdrawal contracture of the opiate-dependent guinea-pig ileum in vitro. These adenosine derivatives also inhibit naloxone-precipitated jumping, diarrhea and weight-loss in morphine-dependent mice. This effect was not due to sedation, since (i) 2-chloroadenosine was effective at a non-sedative dose and (ii) sedative doses of chlordiazepoxide were ineffective.

Topics: 2-Chloroadenosine; Adenosine; Animals; Behavior, Animal; Chlordiazepoxide; Guinea Pigs; Humans; Ileum; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Morphine Derivatives; Muscle Contraction; Myenteric Plexus; Naloxone; Receptors, Cell Surface; Receptors, Purinergic; Substance Withdrawal Syndrome