ABSTRACT
Radioligand binding and behavioral studies were conducted to determine whether a relationship existed between the motor effects produced by (+)-pentazocine and its binding to sigma sites. Scatchard analyses revealed decreased [3H](+)-pentazocine binding in middle aged rats (5-6 months old) compared to young adult rats (2-3 months old). However, there was no difference between the extent of circling behavior or dystonia produced by microinjection of (+)-pentazocine into the substantia nigra or red nucleus in the older animals compared to the young adult rats. There was also a significant decrease in [3H](+)-pentazocine binding in rats chronically treated with haloperidol. Again, however, despite the reduction in [3H](+)-pentazocine binding, there was no difference between the extent of dystonia produced by unilateral intrarubral microinjection of (+)-pentazocine into animals chronically treated with haloperidol vs. saline. The postural changes produced by (+)-pentazocine could not be attenuated with coadministration of the putative sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine), or the opiate receptor antagonist naloxone. However, the (+)-opiate, (+)-nordihydrocodeinone, partially attenuated the postural effects of (+)-pentazocine, despite its very low affinity for sigma 1, sigma 2, or opiate receptors. Taken together with previous studies, the results suggest that [3H](+)-pentazocine is a potent and selective probe for sigma 1 binding sites, but the in vivo effects of (+)-pentazocine cannot be fully attributed to actions through these sites. Some of the in vivo effects of (+)-pentazocine appear to involve other binding sites that are not detected under the conditions normally used in in vitro assays.
Subject(s)
Movement/drug effects , Narcotics/pharmacology , Narcotics/pharmacokinetics , Pentazocine/pharmacology , Pentazocine/pharmacokinetics , Receptors, sigma/physiology , Aging/metabolism , Animals , Central Nervous System Depressants/pharmacology , Dystonia/chemically induced , Dystonia/psychology , Haloperidol/pharmacology , Head Movements/drug effects , In Vitro Techniques , Male , Membranes/drug effects , Membranes/metabolism , Narcotic Antagonists/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, sigma/antagonists & inhibitors , Red Nucleus/drug effects , Red Nucleus/metabolism , Substantia Nigra/drug effects , Substantia Nigra/metabolismABSTRACT
Although diphenhydramine hydrochloride is known to eliminate or reduce the symptoms of dystonia in human patients with acute dystonic reactions and idiopathic torsion dystonia, its mechanism of action is still unclear. In the present study, we show that the antihistamine properties of diphenhydramine may contribute to its beneficial effects. Acute dystonic reactions were produced in rats with unilateral microinjection of haloperidol into the red nucleus as previously described. Similar to the pattern in humans, this effect could be attenuated by coadministration of diphenhydramine. Unilateral microinjection of histamine itself into the rat red nucleus produced dystonic postures (torticollis) in a dose-dependent manner, demonstrating that a histamine dysfunction could contribute to the pathophysiology of dystonia. The torticollis produced by histamine could be significantly attenuated with coadministration of the H1 antagonists diphenhydramine or pyrilamine or the H2 antagonist cimetidine. These effects are thought to be mediated through the red nucleus because significantly more torticollis was observed when histamine was injected into the red nucleus rather than surrounding mid-brain areas, the substantia nigra, or the lateral ventricle. The present data, taken together with studies in humans, suggest the involvement of histamine in some types of dystonia. Furthermore, the red nucleus and related motor pathways may have a more important role in dystonia than previously thought.
Subject(s)
Diphenhydramine/pharmacology , Dystonia/drug therapy , Histamine/pharmacology , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Haloperidol/pharmacology , Male , Movement Disorders/drug therapy , Rats , Rats, Sprague-Dawley , Time Factors , TorticollisABSTRACT
The novel sigma receptor ligands, N(-)[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) and 1(-)[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD1063), were characterized in rats using binding assays and behavioral studies. In radioligand binding studies, the novel ligands showed marked selectivity for sigma binding sites, generally having a 100-fold or better affinity for sigma sites compared to nine other tested receptors (opiate, phencyclidine, muscarinic, dopamine, alpha 1-, alpha 2-, beta-adrenoceptor, 5-HT1, 5-HT2); the only exception was the affinity of BD1047 for beta-adrenoceptors. Competition assays further revealed that the drugs interacted with both sigma 1 and sigma 2 binding sites. Although both drugs had preferential affinities for sigma 1 sites, BD1047 exhibited a higher affinity for sigma 2 sites than BD1063. In behavioral studies, BD1047 and BD1063 had no effects on their own when unilaterally microinjected into the red nucleus of rats, but both compounds attenuated the dystonia produced by the high affinity sigma ligands, di-o-tolylguanidine (DTG) and haloperidol. BD1047 and BD1063 dose-dependently attenuated the dystonia produced by DTG, suggesting a receptor-mediated mechanism, and the dose curve for DTG was shifted to the right in the presence of the novel ligands. BD1047 and BD1063 appear to act as antagonists at sigma sites and may represent promising new tools for probing other functional effects associated with sigma binding sites.
