enkephalin--ala(2)-mephe(4)-gly(5)- and Dyskinesia--Drug-Induced

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

Topics: Animals; Behavior, Animal; Catalepsy; Cell Line; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Drug Administration Routes; Dyskinesia, Drug-Induced; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Globus Pallidus; Humans; Male; Mice; Motor Activity; Naloxone; Narcotic Antagonists; Oligopeptides; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Somatostatin; Transfection

Chronic neuroleptic treatment produces a movement disorder in rats characterized by vacuous chewing movements (VCMs). Neuroleptics also produce a variety of changes in opioid neurotransmission in several regions of the basal ganglia. Rats with the VCM syndrome show elevated mRNA for enkephalin in striatopallidal neurons, suggesting a possible role for enkephalin in the pathophysiology of VCMs.. This study investigated the role of mu-opioid receptor density in the basal ganglia on the expression of VCMs.. Rats were treated with haloperidol for 24 weeks and withdrawn for 9 weeks. Mu (m) receptors were labeled with [3H]-DAMGO.. Haloperidol treatment produced a significant reduction in mu-receptor binding in the globus pallidus (P<0.05). There was, however, no relationship between mu-opioid receptor density and VCMs in this or any other region of the basal ganglia.. These results replicate prior findings of a neuroleptic-induced reduction in [3H]-DAMGO binding in the globus pallidus. The lack of association between VCMs and [3H]-DAMGO binding in the globus pallidus or any other region suggests that prior reports of enkephalinergic mRNA changes in the striatum are not accompanied by compensatory changes in postsynaptic neurons.

Topics: Animals; Antipsychotic Agents; Autoradiography; Behavior, Animal; Dyskinesia, Drug-Induced; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Globus Pallidus; Haloperidol; Male; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Time Factors

Brain opioid systems modulating basal ganglia function may be involved in the development of neuroleptic-induced orofacial dyskinesias. This study examined changes in mu opioid receptors labeled with [3H]D-Ala2, N-MePhe4, Gly-ol5-enkephalin ([3H]-DAMGO) in 79 different brain regions of rats showing vacuous chewing movements after 21 weeks of treatment with haloperidol decanoate (HAL). Dopamine D2 receptors labeled with [3H]raclopride were also examined in the adjacent sections of the same brains. For brain analyses HAL-treated rats were divided into a group showing high incidence of vacuous chewing movements (VCMs) and a group showing low incidence of VCMs. As expected, long-term HAL resulted in a pronounced elevation of D2 receptors in caudate-putamen, n. accumbens, globus pallidus and olfactory bulbs (range: 27.70% increases) compared to controls. These changes were equal in magnitude in both HAL-treated groups, irrespective of the frequency of VCMs. In HAL-treated rats [3H]DAMGO was significantly decreased in several parts of the basal ganglia, including n. accumbens (-21%, P < 0.01), patchy area of the anterior caudate-putamen (-12%, P < 0.05), ventral pallidum (-27%, P < 0.01) and globus pallidus (-21%, P < 0.02). Statistically significant decreases were also seen in the subthalamic nucleus (-12%, P < 0.05) and ventrolateral thalamus (-21%, P < 0.05), both of which are targets of basal ganglia output. However, as in the case of [3H]raclopride binding, [3H]DAMGO changes were generally seen both in the High VCM and the Low VCM groups. These results confirm that long-term haloperidol leads to a decrease in mu-opioid binding in basal ganglia and related structures, similar to what is seen after 6-OHDA denervation. The observed mu-receptor binding changes may be a contribution factor, but do not appear sufficient to account for the differential development of neuroleptic-induced vacuous chewing movements.

Topics: Animals; Antipsychotic Agents; Autoradiography; Brain; Dopamine Antagonists; Dyskinesia, Drug-Induced; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Haloperidol; Male; Mastication; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Opioid, mu; Salicylamides