Motivational Effects of Cannabinoids Are Mediated by -Opioid and-Opioid Receptors
Hans W. D. Matthes,
Brigitte L. Kieffer,
Laboratori de Neurofarmacologia, Facultat de Cie´ncies de la Salut i de la Vida, Universitat Pompeu Fabra, 08003Barcelona, Spain, and
Centre National de la Recherche Scientiﬁque Unite´ Propre de Recherche 9050,Ecole Superieurede Biotechnologie de Strasbourg, 67400 Illkirch, France
Repeated THC administration produces motivational and so-matic adaptive changes leading to dependence in rodents. Toinvestigate the molecular basis for cannabinoid dependenceand its possible relationship with the endogenous opioid sys-tem, we explored 9-tetrahydrocannabinol (THC) activity inmice lacking -, - or -opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion re-mained unaffected in these mice, whereas THC tolerance andwithdrawal were minimally modiﬁed in mutant animals. In con-trast, profound phenotypic changes are observed in severalplace conditioning protocols that reveal both THC rewardingand aversive properties. Absence of receptors abolishes THCplace preference. Deletion of receptors ablates THC placeaversion and furthermore unmasks THC place preference.Thus, an opposing activity of - and -opioid receptors inmodulating reward pathways forms the basis for the dual eu-phoric–dysphoric activity of THC.
Key words: 9-tetrahydrocannabinol; place preference; placeaversion; knock-out; tolerance; dependence; reward
Cannabinoids and opioids are the most widely consumed illicitdrugs worldwide (Smart and Ogborne, 2000). Both types of com- pounds mimic endogenous ligands and act through distinctG-protein-coupled receptor families known as cannabinoid(Felder and Glass, 1998) and opioid (Kieffer, 1995) receptors.Pharmacological studies have shown functional interactions be-tween the two systems (Manzanares et al., 1999). Thus, cannabi-noid and opioid agonists share several pharmacological proper-ties, including antinociception and hypothermia (Narimatsu et al.,1987; Vivian et al., 1998). Biochemical studies have revealed thatrepeated THC administration increases opioid peptide gene ex- pression (Corchero et al., 1997a,b). Acute THC also increasesextracellular levels of endogenous enkephalins in the nucleusaccumbens (Valverde et al., 2001). The existence of cross-tolerance between opioid and cannabinoid agonists has beensupported by a variety of studies. Thus, morphine-tolerant ani-mals show decreased THC antinociceptive responses, whereasTHC-tolerant rodents show a decrease in morphine antinocicep-tion (Hine, 1985; Thorat and Bhargava, 1994). Cross-dependence between opioid and cannabinoid compounds has also been re- ported. Indeed, the opioid antagonist naloxone precipitated a