Drug specificity of pharmacological dystonia.
Three (+)-benzomorphans that bind to sigma receptors produced dystonia in a dose-related manner when microinjected into the red nucleus of rats. Two lines of evidence suggest that these effects were related to the sigma-binding properties of the compounds. First, the behavioral potency of the (+)-benzomorphans and other active sigma compounds correlated highly with their affinities for [3H]1,3-di-o-tolylguanidine-labelled sigma receptors in the rat brain (r = .94). Second, similar intrarubral injections of non-sigma ligands were without effect: various vehicles, a structurally related (+)-opiate with no affinity for sigma receptors, and selective dopaminergic and serotonergic compounds failed to significantly alter the normal posture of rats. The only ligand in this study that binds with high affinity to sigma receptors, but failed to elicit torsional head movements was (+)-[3-(3-hydroxyphenyl)-N-(1-propyl)piperidine] [(+)-3PPP], a ligand with mixed activity at sigma and dopamine receptors. Since (+)-3PPP failed to produce an effect on its own and also failed to attenuate the dystonia produced by another sigma ligand (DTG), it may interact with a non-sigma mechanism or with a different sigma receptor type from the other compounds.
Matsumoto
R R
RR
Schrier Research Laboratory, Department of Psychology, Brown University, Providence, RI 02912.
Hemstreet
M K
MK
Lai
N L
NL
Thurkauf
A
A
De Costa
B R
BR
Rice
K C
KC
Hellewell
S B
SB
Bowen
W D
WD
Walker
J M
JM
D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology*; D004347:Drug Interactions; D004421:Dystonia / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008845:Microinjections; D009019:Morphinans / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017480:Receptors, sigma; D012012:Red Nucleus / Q000187:drug effects* / Q000378:metabolism
D001575:Benzomorphans; D009019:Morphinans; D010880:Piperidines; D011957:Receptors, Opioid; D017480:Receptors, sigma; C026539:preclamol