RT Journal Article SR Electronic T1 HINDLIMB REFLEXES OF CHRONIC SPINAL DOGS DURING CYCLES OF ADDICTION TO MORPHINE AND METHADON JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 382 OP 400 VO 94 IS 4 A1 ABRAHAM WIKLER A1 KARL FRANK YR 1948 UL http://jpet.aspetjournals.org/content/94/4/382.abstract AB 1. Methods for preparing long-surviving, chronic spinal dogs, and methods for recording spontaneous activity and hindlimb reflexes in such preparations are described. 2. In chronic spinal dogs, single doses of morphine or methadon depress markedly the ipsilateral flexor and crossed extensor reflexes, enhance the ipsilateral extensor thrust in most instances, and have small but variable effects on the knee jerk. After very large doses of morphine (100-150 mgm./kgm.) or methadon (40-50 mgm./kgm.) tonic and clonic convulsions appear in the segments rostral to the transection but not below it. 3. During addiction to morphine or methadon, tolerance develops to the depressant effects of morphine and methadon on the ipsilateral flexor and crossed extensor reflexes, but not to the excitant effects on the ipsilateral extensor thrust. As addiction is continued, the pre-injection values of the ipsilateral flexor and crossed extensor reflexes increases, both with respect to amplitude and duration of the response. 4. After abrupt cessation of morphine or methadon, the ipsilateral flexor and crossed extensor reflexes continue to increase in magnitude, while the knee jerk and ipsilateral extensor thrusts diminish markedly. Spontaneous rhythmic activity appears in the hindlimbs (dog in lateral recumbent position) as early as 30½ hours after withdrawal of morphine and 9 hours after withdrawal of methadon. This activity increases in magnitude and frequency until a peak is reached about the 72nd.-9Oth. hour after morphine and about the 24th-3Oth hour after methadon withdrawal, following which there is a gradual return of the hindlimbs to the pre-addiction status over a period of 10-14 days. However, hyperactivity of the ipsilateral flexor reflex may persist for as long as 4 months after withdrawal of morphine. 5. After withdrawal of morphine or methadon, general signs of abstinence such as restlessness, tremors, fever, yawning, vomiting, lacrimation, rhinorrhea, and occasionally diarrhea appear at about the same time as the spontaneous activity in the hindlimbs. These general signs also reach a peak at about the same time as the hindlimb spontaneous activity, but they subside much more rapidly than the changes in reflexes which occur during The withdrawal period. 6. The effects of sodium pentobarbital, neostigmine, eserine, and elevation of body temperature on the hindlimbs of chronic spinal dogs are described. 7. The data are discussed with reference to the problems of loci of action of morphine and methadon, theories of physical dependence, and studies of physical dependence-producing liability of drugs. 1948 by The American Society for Pharmacology and Experimental Therapeutics