Involvement of kappa-opioid receptors and sigma receptors in memory function demonstrated using an antisense strategy.
Although antinociceptive effects of U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulfonate and (-)-pentazocine have been reported to influence kappa-opioid receptors, the involvement of kappa-opioid receptors in learning and/or memory is still controversial. We have recently reported that the memory improving effect of (-)-pentazocine was antagonized by sigma1 receptor antagonist. In this study, we examined the effects of several antisense oligodeoxynucleotides (antisenses) to kappa1-opioid receptors and sigma1 receptor on memory and nociceptive function. Male ddY mice were treated subcutaneously (s.c.) with scopolamine (1.65 mumol/kg) and/or test drugs 30 min before a Y-maze test. U-50,488H significantly improved the scopolamine-induced impairment of spontaneous alternation behavior. Twenty micrograms of antisense targeting exons 2 and 3 of the kappa1-opioid receptor significantly reversed the effects of U-50,488H, but antisense targeting exon 1 and mismatch sense did not. The antisense targeting exon 3 was most effective. These antisenses themselves did not affect normal mice, indicating that kappa1-opioid receptors do not tonically regulate memory function. All three antisenses equally prevented U-50,488H-induced antinociceptive effects in the acetic-acid-induced writhing test. Pretreatment with antisense targeting sigma1 receptors (AS-sigma1) completely prevented the memory-improving effects of (-)- and (+)-pentazocine, although U-50,488H ameliorated the scopolamine-induced impairment of spontaneous alternation behavior in AS-sigma1-treated mice. These results suggest that kappa1-opioid receptors containing different exons have a distinct function in memory and nociceptive functions. Furthermore, kappa-opioid receptors agonist showing analgesic effects act on kappa-opioid receptors or sigma receptors and play important roles only when memory function is impaired, but the two neuronal systems regulate memory function independently.
Hiramatsu
Masayuki
M
Laboratory of Neuropsychopharmacology, Graduate School of Environmental and Human Sciences, Meijo University, Tenpaku-ku, Nagoya 468-8503, Japan. mhiramt@ccms.meijo-u.ac.jp
Hoshino
Takashi
T
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000139:chemically induced; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000502:physiology*; D017480:Receptors, sigma / Q000502:physiology*; D012601:Scopolamine
D018712:Analgesics, Non-Narcotic; D020319:Oligodeoxyribonucleotides, Antisense; D017473:Receptors, Opioid, kappa; D017480:Receptors, sigma; C116587:kappa(1) opioid receptor; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D012601:Scopolamine