Allosteric modulation of α4β2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain

Autor: D. Ergun, Wisam Toma, Deniz Bagdas, M.I. Damaj, Marvin K. Schulte, Asti Jackson
Přispěvatelé: Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi., Bağdaş, Deniz
Rok vydání: 2017
Předmět:
Disease mkodels
animal
Male
0301 basic medicine
Beta-2
Unclassified drug
Mouse
Receptors
Nicotinic
Pharmacology
Ligands
Neuropathic pain
Nicotinic receptor alpha4beta2
Indole Alkaloids
Antinociception
Nicotine
Nicotinic receptor
Mice
chemistry.chemical_compound
Sensitivity
0302 clinical medicine
Anesthesiology
Abt-594
Drug activity
Allosterism
Nicotinic Agonists
Priority journal
Desformylflustrabromine
Morphine
Nicotinic agent
Stoichiometry
Hydrocarbons
Brominated
Antiallodynic effect
Megadose
Nicotinic agonist
Indole alkaloid
Clinical neurology
Brominated hydrocarbon
Bromine derivative
Locomotion
medicine.drug
Epibatidine
Nicotinic Receptors
Mecamylamine
Agonist
Allosteric modulator
Efficacy
medicine.drug_class
Drug potentiation
Neurosciences & neurology
Concentration response
Allodynia
Partial agonist
Article
Chronic constriction injury
Low drug dose
Rotarod test
03 medical and health sciences
Allosteric Regulation
Discriminative-stimulus
medicine
Animals
Animal model
Animal experiment
Cholinergic activity
Animal
Disease model
business.industry
Motor dysfunction
Neurosciences
Nonhuman
Drug effect
Disease Models
Animal
Metabolism
030104 developmental biology
Anesthesiology and Pain Medicine
nervous system
chemistry
Motor coordination
Neuralgia
Cholinergic
sense organs
business
Controlled study
Neuroscience
030217 neurology & neurosurgery
NS9283
Zdroj: Eur J Pain
ISSN: 1090-3801
Popis: BackgroundNeuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The 42 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of 42 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for 42 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at 42 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception. MethodsThe present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine-evoked antiallodynic response. ResultsWe found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour dose- and time-dependently without motor impairment. Our data revealed that this effect was mediated by the 42 nAChRs by using competitive 42 antagonist dihydro--erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to 42 nAChRs. ConclusionsThe present results suggest that allosteric modulation of 42 nAChR may provide new strategies in chronic neuropathic pain. Significance42 nAChRs are involved in pain modulation. dFBr, a PAM at 42 nAChRs, potentiates the nicotine response dose-dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of 42* nAChR may provide new strategies in chronic neuropathic pain. United States Department of Health & Human Services National Institutes of Health (NIH) - USA (R01-CA206028) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) (R01CA206028)
Databáze: OpenAIRE
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