THC withdrawal upon chronic THC treatment was reduced in pEnk KO mice (Valverde et al., 2000) and double mu-delta KO mice (Castane et al., 2003). Reduced THC withdrawal was also detected in mu KO animals, at high doses of THC (Lichtman et al., 2001). Single mutants for pDyn (Zimmer et al., 2001), mu, delta or kappa receptors (Ghozland et al., 2002) otherwise showed normal THC withdrawal. The data together suggest that an endogenous enkephalinergic tone, acting jointly at mu and delta receptors, contributes to the development of physical dependence to THC.
