Yohimbine co-treatment during chronic morphine administration attenuates naloxone-precipitated withdrawal without diminishing tail-flick analgesia in rats

Abstract

Noradrenergic neuronal hyperactivity following chronic morphine administration has been postulated to cause withdrawal signs and symptoms. Suppression of this hyperactivity, for example, by clonidine attenuates withdrawal. It might follow, therefore, that the prevention of suppression of noradrenergic systems during chronic morphine administration might diminish hyperactivity and prevent withdrawal. If the normalization of noradrenergic activity during opioid administration did not also suppress analgesia, it might be of medical and theoretical interest. To test this hypothesis, we gave the alpha-2-antagonist yohimbine to rats in order to increase noradrenergic activity during morphine treatment and then subsequently precipitated morphine withdrawal with naloxone. Six groups were examined: saline controls (N=11), morphine (N=11), morphine + 2.0 mg/kg/day yohimbine (N=15), morphine + 3.0 mg/kg/day yohimbine (N=5), 2.0 mg/kg/day yohimbine (N=11) and 3.0 mg/kg/day yohimbine (N=5). Subjects received 75 mg morphine pellets implanted on day 1,4 and 6 of the treatment or sham implantation. Yohimbine was delivered throughout the morphine treatment by subcutaneously implanted osmotic pumps. On day 7, all subjects were given 1.0 mg/kg naloxone and rated for behavioral signs of withdrawal. Analgesia was measured by observing tail flick latencies (TFL) before and after chronic drug treatments. Naloxone-precipitated withdrawal was characterized by irritability, ptosis, penile erection, diarrhea, rhinorrhea, abnormal posture, wetdog shakes, jumping, and teeth chattering, none of which were observed in groups receiving only saline or yohimbine. Withdrawal behavior was attenuated in a dose-dependent manner when yohimbine was administered during morphine treatment but analgesia was not attenuated. It appears that yohimbine-induced antagonism of alpha-2-adrenergic receptors diminishes the development of the potential for adrenergic hyperactivity and morphine withdrawal without reducing opioid analgesia.