Antinociceptive mechanism of the spirocyclopiperazinium compound LXM-10 in mice and rats.
Drugs typically used to treat pain are limited by their undesirable side effects, which has prompted a search for mechanistically different analgesic agents. We report the antinociception effect of the spirocyclopiperazinium compound LXM-10 via activation of peripheral alpha7 nicotinic and muscarinic acetylcholine receptors in mice. This effect was attenuated by hexamethonium, atropine methylnitrate, methyllycaconitine citrate, tropicamide, bicuculline, and phaclofen. Competition receptor-binding assays in vitro showed that LXM-10 binds with high affinity alpha7 nAchR and with low affinity M4 receptors. Our findings show that the antinociception signaling pathway of LXM-10 underlies activation of peripheral alpha7 nicotinic and possibly of M4 muscarinic receptors, which activate GABA(A) and GABA(B) receptors, resulting in antinociceptive effects without obvious side effects.
Xiong
Yulan
Y
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China.
Zhao
Xia
X
Sun
Qi
Q
Li
Runtao
R
Li
Changling
C
Ye
Jia
J
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*
C547090:2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro(5.5)undecane chloride; D000700:Analgesics; D010879:Piperazines; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D013141:Spiro Compounds