Linked Life Data

21620806

Source:http://linkedlifedata.com/resource/pubmed/id/21620806

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2011-8-25
pubmed:abstractText
Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) ?4?2 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 ?mol/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 ?mol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the ?4?2 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 ?4?2 nAChR by PAM may represent a novel analgesic approach.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1873-2968
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 Elsevier Inc. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
82
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
967-76
pubmed:meshHeading
pubmed-meshheading:21620806-Allosteric Regulation, pubmed-meshheading:21620806-Analgesics, pubmed-meshheading:21620806-Animals, pubmed-meshheading:21620806-Azetidines, pubmed-meshheading:21620806-Behavior, Animal, pubmed-meshheading:21620806-Body Temperature, pubmed-meshheading:21620806-Brain, pubmed-meshheading:21620806-Disease Models, Animal, pubmed-meshheading:21620806-Drug Therapy, Combination, pubmed-meshheading:21620806-Magnetic Resonance Imaging, pubmed-meshheading:21620806-Male, pubmed-meshheading:21620806-Nicotinic Agonists, pubmed-meshheading:21620806-Osteoarthritis, pubmed-meshheading:21620806-Oxadiazoles, pubmed-meshheading:21620806-Pain, pubmed-meshheading:21620806-Pyridines, pubmed-meshheading:21620806-Rats, pubmed-meshheading:21620806-Rats, Sprague-Dawley, pubmed-meshheading:21620806-Receptors, Nicotinic
pubmed:year
2011
pubmed:articleTitle
Potentiation of analgesic efficacy but not side effects: co-administration of an ?4?2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats.
pubmed: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
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't