Sigma sites mediate DTG-evoked hypothermia in rats.
1,3,-Di-o-tolylguanidine (DTG), a sigma agonist, produces hypothermia in rats, but the inability of purported sigma antagonists to block the hypothermia suggests that sites other than sigma may mediate the effect. Recently, N-[2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD 1047) has been identified as a functional sigma antagonist in vivo because of its high selectivity for sigma sites and its ability to block DTG-induced dystonia and cocaine-evoked behaviors. Therefore, the present study investigated the effect of BD 1047 on DTG-evoked hypothermia. DTG (1, 10, 20 and 30 mg/kg sc) induced dose-dependent hypothermia. The onset of DTG-induced hypothermia was rapid, with a reduction in body temperature observed 15 min postinjection. To determine whether sigma sites mediated DTG-induced hypothermia, BD 1047 was injected 30 min prior to DTG. BD 1047 (1, 5, 7.5 and 10 mg/kg sc) attenuated the hypothermia in a dose-dependent fashion, thus revealing a sigma site mechanism. The injection of BD 1047 alone did not alter body temperature, suggesting that endogenous sigma systems do not play a tonic role in thermoregulation. The present experiments demonstrate for the first time that a selective sigma antagonist attenuates sigma agonist-induced hypothermia. Moreover, these data provide further evidence that BD 1047 is an effective antagonist for characterizing sigma-mediated effects in vivo.
Rawls
S M
SM
Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA. smrawls28@hotmail.com
Baron
David A
DA
Geller
Ellen B
EB
Adler
Martin W
MW
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D005029:Ethylenediamines / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D007035:Hypothermia / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology
D005029:Ethylenediamines; D006146:Guanidines; D017480:Receptors, sigma; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C050232:1,3-ditolylguanidine