MD-354 selectively antagonizes the antinociceptive effects of (-)nicotine in the mouse tail-flick assay.
BACKGROUND
(-)Nicotine produces antinociceptive effects in rodents. meta-Chlorophenylguanidine (MD-354), an analgesia-enhancing agent, binds at 5-HT(3) and alpha(2)-adrenoceptors and potentiates the antinociceptive effects of an "inactive" dose of clonidine. The present study examined the actions of MD-354 on (-)nicotine-induced antinociception.


METHODS
Mouse tail-flick and other assays were employed.


RESULTS
In the tail-flick assay, (-)nicotine (ED(50) = 1.66 mg/kg) but not MD-354 produced dose-related antinociceptive effects. Administered in combination with (-)nicotine (2.5 mg/kg), MD-354 (AD(50) = 3.4 mg/kg) did not potentiate, but effectively antagonized the antinociceptive actions of (-)nicotine. In a mouse hot-plate assay, MD-354 failed to modify (-)nicotine responses. In combination with a locomotor activity-suppressing dose of (-)nicotine, MD-354 (up to 17 mg/kg) failed to antagonize (-)nicotine-induced hypolocomotion. In a rat drug discrimination paradigm using (-)nicotine as training drug, MD-354 produced saline-appropriate responding; in combination with the training dose of (-)nicotine, MD-354 failed to antagonize the nicotine cue.


CONCLUSIONS
MD-354 selectively antagonizes the antinociceptive actions of (-)nicotine in the tail-flick, but not in the hot-plate assay, or either the motor effects, or discriminative stimulus effects of (-)nicotine. The most parsimonious explanation is that MD-354 might act as a negative allosteric modulator of alpha 7 nACh receptors, and radioligand binding and functional data are provided to support this conclusion.
Dukat
Małgorzata
M
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Box 980540, Richmond, VA 23298-0540, USA. mdukat@vcu.edu
Wesołowska
Anna
A
Alley
Genevieve
G
Young
Shawquia
S
Abdrakhmanova
Galya R
GR
Navarro
Hernán A
HA
Young
Richard
R
Glennon
Richard A
RA
D000700:Analgesics / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000378:metabolism; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006146:Guanidines / Q000032:analysis / Q000494:pharmacology*; D006801:Humans; D007456:Iodine Isotopes / Q000032:analysis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D006146:Guanidines; D007456:Iodine Isotopes; C495409:m-chlorophenylguanidine; D009538:Nicotine