n(6)-cyclohexyladenosine and Substance-Withdrawal-Syndrome

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

Adenosine reduces opioid withdrawal symptoms by activating A(1) adenosine receptors, probably by inhibiting excitatory amino acid release. Since blockade of A(2A) adenosine receptors seems to enhance dopaminergic striatopallidal transmission, we evaluated the role of the purinergic system in the opiate withdrawal syndrome by using two A(1) receptor agonists [ N(6)-cyclohexyladenosine, CHA and 2-chloro- N(6)-cyclopentyladenosine, CCPA], and two A(2A) receptor antagonists (SCH 58261 and 8-(3-chlorostyryl)caffeine, CSC). Male adult rats received increasing doses of morphine sulphate suspended in 5 ml/kg of a sustained release preparation (40-100 mg/kg s.c.) daily for 4 days and 20 h after the last administration, the withdrawal syndrome was evoked by naloxone (5 mg/kg i.p.). Animals were observed for 30 min for signs of opiate withdrawal. Other groups of rats were implanted with concentric probes for microdialysis and dopamine levels were measured in the nucleus accumbens. CHA and CCPA (0.05, 0.1 or 0.5 mg/kg i.p.) significantly reduced "wet-dog" shakes, diarrhoea, teeth chattering, jumping and writhing. SCH 58261 and CSC (0.1, 0.5 or 1 mg/kg i.p.), given 10 min before naloxone, also reduced signs of opiate withdrawal. CHA plus SCH 58261 and CCPA plus CSC greatly enhanced the reduction of withdrawal signs observed with CHA and CCPA or CSC and SCH 58261 alone. In vivo microdialysis showed that naloxone significantly decreased DA release; this effect was prevented by pretreatment with systemic SCH 58261 and CSC, but not with CHA and CCPA. Our results demonstrate that A(1) and A(2A) adenosine receptors mediate the effect induced by adenosine in opiate withdrawal syndrome and suggest that adenosine A(1) agonists and adenosine A(2A) antagonists may be beneficial in the treatment of this syndrome.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Caffeine; Chromatography, High Pressure Liquid; Dopamine; Injections, Subcutaneous; Male; Microdialysis; Morphine; Pyrimidines; Rats; Rats, Wistar; Receptors, Dopamine; Substance Withdrawal Syndrome; Triazoles

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