Inhibition of naloxone-resistant antinociception by centrally administered H2-antagonists.
In order to test directly the hypothesis that brain histamine and H2-receptors mediate the naloxone-resistant footshock-induced antinociception (FSIA) elicited by 3 min of 3.5 mA, the effect of i.c.v. H2-antagonists on this response was determined. Intracerebroventricular zolantidine dimaleate produced an inhibition of the response that was both time- and dose-dependent, with no effect on base-line responses. A dose of 20 micrograms produced maximal (93%) inhibition of FSIA when given 10 min before footshock, with a calculated ID50 of 7.18 nmol. Eight additional H2-antagonists with varying structures and brain-penetrating qualities also exhibited dose-dependent inhibition of the response with no effect on base-line nociception. The potencies of these compounds for inhibition of naloxone-resistant FSIA correlated significantly (r = 0.966, P less than .001; rho = 0.980, P less than .002) with their affinities at the H2-receptor, providing strong support for the hypothesis that brain histamine and H2-receptors are important components of naloxone-resistant FSIA.
Gogas
K R
KR
Department of Pharmacology and Toxicology, Albany Medical College, New York.
Hough
L B
LB
D000698:Analgesia; D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006632:Histamine / Q000502:physiology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D008297:Male; D009270:Naloxone / Q000494:pharmacology*; D050198:Phenoxypropanolamines; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D006635:Histamine H2 Antagonists; D050198:Phenoxypropanolamines; D010880:Piperidines; D013844:Thiazoles; D009270:Naloxone; D006632:Histamine; C055302:zolantidine