Effects of α7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models.
Agonists and positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for managing cognitive deficits in schizophrenia and Alzheimer's disease. Though α7 agonists were recently found to possess antinociceptive and anti-inflammatory properties in rodent models of chronic neuropathic pain and inflammation, the effects of α7 nAChRs PAMs on chronic pain and inflammation remain largely unknown. The present study investigated whether PAMs, by increasing endogenous cholinergic tone, potentiate α7 nAChRs function to attenuate inflammatory and chronic neuropathic pain in mice. We tested two types of PAMS, type I (NS1738) and type II (PNU-120596) in carrageenan-induced inflammatory pain and chronic constriction injury (CCI) neuropathic pain models. We found that both NS1738 and PNU-120596 significantly reduced thermal hyperalgesia, while only PNU-120596 significantly reduced edema caused by a hind paw infusion of carrageenan. Importantly, PNU-120596 reversed established thermal hyperalgesia and edema induced by carrageenan. In the CCI model, PNU-120596 had long-lasting (up to 6 h), dose-dependent anti-hyperalgesic and anti-allodynic effects after a single injection, while NS1738 was inactive. Systemic administration of the α7 nAChR antagonist MLA reversed PNU-120596's effects, suggesting the involvement of central and peripheral α7 nAChRs. Furthermore, PNU-120596 enhanced an ineffective dose of selective agonist PHA-543613 to produce anti-allodynic effects in the CCI model. Our results indicate that the type II α7 nAChRs PAM PNU-120596, but not the type I α7 nAChRs PAM NS1738, shows significant anti-edematous and anti-allodynic effects in inflammatory and CCI pain models in mice.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA.
Kelen
K
Freitas
Sudeshna
S
Ghosh
F
F
Ivy Carroll
Aron H
AH
Lichtman
M
M
Imad Damaj
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000188:drug therapy*; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D011978:Receptors, Nicotinic / Q000502:physiology*; D016896:Treatment Outcome; D064569:alpha7 Nicotinic Acetylcholine Receptor
C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C523981:1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea; D000700:Analgesics; C579166:Chrna7 protein, mouse; D007555:Isoxazoles; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor