title: Potentiation of analgesic efficacy but not side effects: co-administration of an α4β2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats.
abstract: Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4β2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 μmol/kg, i.p.) induced a 6-fold leftward shift of the dose-response of ABT-594 (ED(50)=26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED(50)=26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED(50)=1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose-response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 μmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4β2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4β2 nAChR by PAM may represent a novel analgesic approach.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. Chang.Z.Zhu@abbott.com
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Chih-Liang
authors.initials: CL
authors.lastname: Chin
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Rustay
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Joe
authors.initials: J
authors.lastname: Mikusa
authors.forename: Prasant
authors.initials: P
authors.lastname: Chandran
authors.forename: Anita
authors.initials: A
authors.lastname: Salyers
authors.forename: Erica
authors.initials: E
authors.lastname: Gomez
authors.forename: Gricelda
authors.initials: G
authors.lastname: Simler
authors.forename: La Geisha
authors.initials: LG
authors.lastname: Lewis
authors.forename: Donna
authors.initials: D
authors.lastname: Gauvin
authors.forename: Scott
authors.initials: S
authors.lastname: Baker
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.forename: Ann
authors.initials: A
authors.lastname: Tovcimak
authors.forename: Jordan
authors.initials: J
authors.lastname: Brown
authors.forename: Victoria
authors.initials: V
authors.lastname: Komater
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Michael W
authors.initials: MW
authors.lastname: Decker
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
mesh_terms: D000494:Allosteric Regulation; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008279:Magnetic Resonance Imaging; D008297:Male; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: C561896:3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D000700:Analgesics; D001384:Azetidines; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2