Improgan, a cimetidine analog, induces morphine-like antinociception in opioid receptor-knockout mice

Improgan is an analog of the H-2 antagonist cimetidine that does not act on known histamine receptors, but induces highly effective analgesia in roden ts following intracerebroventricular (icv) administration. Since the mechan ism of action of this compound remains unknown, improgan analgesia was char acterized presently with the tail immersion nociceptive test in mutant mice lacking either the mu. (exon 1 of MOR-1), delta (exon 2 of DOR-1) or kappa (exon 3 of KOR-1) opioid receptor. Improgan (30 mug, icy) induced reversib le, maximal analgesia in both sexes of all three genotypes (+/+, +/- and -/ -) of MOR-1 mutant mice 10 and 20 min after administration, whereas morphin e analgesia was reduced (+/-) or abolished (-/-) in these subjects. In DOR- 1 mutant mice, improgan was equally effective in all three genotypes, despi te the reduction (+/-) or complete loss (-/-) of delta opioid receptor (H-3 -[D-Pen(2),D-Pen(5)]enkephalin. DPDPE) binding. Similarly, improgan analges ia was equivalent in all three genotypes of KOR-1 mutant mice, whereas kapp a -mediated analgesia (U50,488) and kappa opioid (H-3-U69,593) binding were abolished in the homozygous (-/-) mice. These studies demonstrate that imp rogan analgesia does not require intact MOR-I, DOR-1. or KOR-I genes, and s upport the hypothesis that improgan-like analgesics act in the CNS by non-o pioid mechanisms. (C) 2000 Elsevier Science B.V. All rights reserved.