Effects of alpha-adrenoceptor agonists in chronic morphine administered DSP4-treated rats: evidence for functional cross-sensitization.

Abstract

Five experiments were performed to study the effects of the Alpha-adrenoceptor agonists, clonidine and guanfacine, upon spontaneous motor activity in chronically morphine administered DSP4-treated and control rats. DSP4 (2 x 50 mg/kg, with a 10-day interval between injections) and vehicle (distilled water) were injected i.p., on each occasion 30 min after zimeldine (20 mg/kg). Morphine dosages were raised incrementally from 5 mg/kg (Days 1-3), through 10 mg/kg (Days 4-7) and 20 mg/kg (Days 8-14), to 30 mg/kg (Days 15-20). Motor activity testing occurred on Day 21, Day 22 as well as in Experiments II-V, (from 1st morphine injection). DSP4 pretreatment and chronic morphine injections each reduced motor activity during the first 30 min of testing; combined DSP4 and morphine treatment potentiated the hypoactivity. Habituation quotients indicated deficits in habituation to the novel test environment by the Vehicle-morphine (Quoteint2 only) and DSP4-morphine groups. Acute clonidine treatment (0.04 mg/kg s.c.) reduced motor activity during the first 30 min of testing but attenuated or blocked the morphine-induced hypoactivity in DSP4-treated and control rats. During the 60-90 min test period, clonidine, but not guanfacine (0.08 mg/kg), potentiated morphine-induced hyperactivity in control rats; acute clonidine enhanced this effect, whereas acute guanfacine reduced it, in the DSP4-treated rats. The enhanced hyperactivity of morphine-clonidine suggest a cross-sensitivity effect. Naloxone (0.1 mg/kg s.c.), injected after the 1st 30-min of testing, potentiated markely the clonidine-induced elevations of motor activity in morphine-administered control rats; in the DSP4-treated rats, these effects were dramatically potentiated, underlining the cross-sensitivity effect. Acute guanfacine treatment reduced motor activity during the first 30 min of testing but did not attenuate reliably morphine-induced hypoactivity in control or DSP4 rats. Naloxone did not potentiate the guanfacine-induced hyperactivity of morphine-administered control rats but induced a marked enhancement in the DSP4-treated rats, a specific case of cross-reactivity. The major findings pertain to a cross-sensitization effect of morphine upon clonidine-induced motor activity in both DSP4-treated and control rats, and to a lesser extent between morphine and guanfacine in NA-denervated rats only. The results may offer interactive implications for noradrenergic-opiate system functioning that may be of influence under neuropathological conditions.