Participation of different brain regions in the anti-narcotic withdrawal action of clonidine in the dependent rat

Abstract

The naloxone-precipitated withdrawal response in morphine dependent rats was quantitated by measuring the post-withdrawal increase in mean arterial pressure (MAP), heart rate and several characteristic behavioral changes. Pretreatment with intrathecal injection of clonidine produced a significant reduction in most of the autonomic symptoms of withdrawal, including the increase in MAP, salivation, and chromodacryorrhea, but did not effect the behavioral signs, body shakes, escape attempts or teeth chattering. Central i.c.v. injection of clonidine also reduced the autonomic symptoms of withdrawal. Two differences between the two routes of clonidine administration were with respect to (1) the degree of hind limb kicking where i.t., but not i.c.v. administration was effective at reducing this symptom; and (2) i.c.v., but not i.t. clonidine was effective in significantly reducing the incidence of diarrhea. In contrast, intracisternal (medullary level) injection of clonidine was without effect on the post-withdrawal increase in MAP, and inhibitory effects on the other symptoms included only salivation and diarrhea. Thus the effect of clonidine following intrathecal injection was not due to redistribution of drug to higher centers. Direct intrathecal injection of naloxone also precipitated withdrawal in morphine dependent rats. In this case, intrathecal pretreatment with clonidine did not inhibit the post-withdrawal increase in MAP. These results are consistent with a spinal component for the autonomic and behavioral symptoms of morphine withdrawal in the rat. Clonidine's antiwithdrawal response is mediated at least in part through a spinal action. However, this spinal antiwithdrawal action of clonidine is selective for withdrawal responses which originate from supraspinal centers.