Caffeine increases paragigantocellularis neuronal firing rate and induces withdrawal signs in morphine-dependent rats.

Using single unit recording in nucleus paragigantocellularis neurons located in the rostral ventrolateral medulla, and measuring the precipitated withdrawal syndrome, we investigated whether chronic morphine administration would produce adaptive changes in the adenosine system. Caffeine (50 mg/kg, i.p.) induced withdrawal signs (head shakes, tooth chattering, ejaculation, chewing, and irritability) in morphine-dependent rats 10-18 min after the injection. Only the tooth chattering and diarrhea were expressed following a direct paragigantocellularis injection of caffeine (200 microM, 0.5 microl). The spontaneous activity of paragigantocellularis neurons was significantly decreased by microinjection of both adenosine (10 nM) and an adenosine A1 receptor-selective agonist, cyclohexyladenosine (200 microM), into the paragigantocellularis nucleus of both control and morphine-dependent rats, but the decrease in firing rate of paragigantocellularis neurons of morphine-dependent rats was greater than that of control ones. There was also a significant enhancement of spontaneous activity of paragigantocellularis neurons 8-15 min after caffeine administration (50 mg/kg, i.p.) and 10-18 min after the injection of an adenosine A1 receptor-selective antagonist 8-phenyltheophylline (10 mg/kg, i.p.) in both control and morphine-dependent rats. However, the effect of the antagonists was greater in morphine-dependent rats than in control ones. These data suggest that there is an increase in the sensitivity of nucleus paragigantocellularis neurons to adenosine receptor ligands in morphine-dependent rats that may be associated with the ability of caffeine to produce withdrawal signs.