Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice.
The biochemical processes underlying opiate addiction are complex, but n-methyl-d-aspartate receptor (NMDAR) dysfunction appears to be one contributing factor. NMDAR antagonists, including MK-801 and memantine, have previously been shown to assuage symptoms stemming from opiate withdrawal. The conantokins are a small family of naturally occurring peptide toxins known to specifically antagonize the NMDAR. In the present study, the effects of wild-type and variant conantokins on the suppression of naloxone-induced jumping in morphine-dependent mice were evaluated. Our results demonstrate that NR2B-selective conantokins, viz., con-G, con-G[S(16)Y] and con-G[gamma(7)K], are potent inhibitors of naloxone-induced jumping at low doses (2-15 nmol/kg) compared with con-T, con-R[1-17], and small-molecule antagonists of the NMDAR, including the NR2B-selective agent, ifenprodil. We conclude that the NR2B-selective conantokins may find utility as neuropharmacological tools for probing NMDAR-related mechanisms of opiate dependence.
Wei
Juanjuan
J
Beijing Institute of Biotechnology, Beijing 100071, China.
Dong
Mingxin
M
Xiao
Cai
C
Jiang
Fengchao
F
Castellino
Francis J
FJ
Prorok
Mary
M
Dai
Qiuyun
Q
D000818:Animals; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008978:Mollusk Venoms / Q000737:chemistry / Q000494:pharmacology*; D009021:Morphine Dependence / Q000503:physiopathology*; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D020916:Conotoxins; D036341:Intercellular Signaling Peptides and Proteins; D008978:Mollusk Venoms; C121001:NR2B NMDA receptor; D009292:Narcotic Antagonists; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C403083:conantokin R; C063571:conantokin-T; D009270:Naloxone; C055407:conotoxin GV