RX 336-M, a new chemical tool in the analysis of the quasi-morphine withdrawal syndrome.

RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone) and four other chemically-diverse agents--AG-3-5 (1-[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one), Sgd 8473 (alpha-[4-chlorobenzylideneamino)-oxy]-isobutyric acid), thyrotropin releasing hormone (TRH), and sodium valproate--each induce signs of withdrawal, most notably 'wet-dog' shaking, after acute i.p. administration in drug-naive rats. They are therefore additions to a recently recognized and, as yet, ill-defined class of behaviorally active compounds. The pharmacological baselines that link these disparate agents together have been studied in the present work, using 'wet-dog' shaking as the behavioral measure and RX 336-M as the reference shake-inducing compound. Peripheral administration of clonidine, haloperidol, d-lysergic acid diethylamide, or morphine suppressed chemically induced shaking: naloxone had no marked effect. Reverse tolerance was associated with TRH-induced shaking whereas tolerance occurred with the other four compounds. Cross-tolerance interactions were asymmetrical. Thus, rats rendered tolerant to RX 336-M were cross-tolerant to AG-3-5, TRH, and sodium valproate but not to Sgd 8473; in contrast, RX 336-M-induced shaking was only significantly reduced in rats made tolerant to Sgd 8473. In view of the unidirectional nature of the cross-tolerance relationships studied, it is concluded that AG-3-5, Sgd 8473, sodium valproate, and TRH initiate 'wet-dog' shaking through neural substrates that differ from the one(s) associated with RX 336-M. Nevertheless, all five compounds may eventually trigger a common shake-inducing mechanism.