Endomorphin-1: Induction of motor behavior and lack of receptor desensitization

The endomorphins are recently discovered endogenous agonists for the mu -op ioid receptor (Zadina et al., 1997). Endomorphins produce analgesia; howeve r, their role in other brain functions has not been elucidated. We have inv estigated the behavioral effects of endomorphin-1 in the globus pallidus, a brain region that is rich in mu -opioid receptors and involved in motor co ntrol. Bilateral administration of endomorphin-1 in the globus pallidus of rats induced orofacial dyskinesia. This effect was dose-dependent and at th e highest dose tested (18 pmol per side) was sustained during the 60 min of observation, indicating that endomorphin-1 does not induce rapid desensiti zation of this motor response. In agreement with a lack of desensitization of mu -opioid receptors, 3 hr of continuous exposure of the cloned mu recep tor to endomorphin-1 did not diminish the subsequent ability of the agonist to inhibit adenylate cyclase activity in cells expressing the cloned mu -o pioid receptor. Confirming the involvement of mu -opioid receptors, the beh avioral effect of endomorphin-1 in the globus pallidus was blocked by the o pioid antagonist naloxone and the mu -selective peptide antagonist Cys(2)-T yr(3)-Orn(5)-Pen(7) amide (CTOP). Furthermore, the selective mu receptor ag onist [D-Ala(2)-N-Me-Phe(4)Glycol(5)]- enkephalin (DAMGO) also stimulated o rofacial dyskinesia when infused into the globus pallidus, albeit transient ly. Our findings suggest that endogenous mu agonists may play a role in hyp erkinetic movement disorders by inducing sustained activation of pallidal o pioid receptors.