D Bagdas1,2, J A Meade1, Y Alkhlaif1, P P Muldoon1, F I Carroll3, M I Damaj1. 1. Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA. 2. The Center for the Study for Tobacco Products, Virginia Commonwealth University, Richmond, USA. 3. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, USA.
Abstract
BACKGROUND: Preclinical assays of affective and sensorial aspects of nociception play a key role in research on both the neurobiology of pain and the development of novel analgesics. Therefore, we investigated the effects of nicotine and alpha-7 nicotinic acetylcholine receptor (nAChR) modulators in the negative affective and sensory components of visceral pain in mice. METHODS AND RESULTS: Intraperitoneal acetic acid (AA) administration resulted in a robust stretching behaviour and conditioned place aversion (CPA) in mice. We observed a dose-dependent reduction in AA-induced stretching and CPA by the nonselective nAChRs agonist nicotine. Mecamylamine, a nonselective nAChRs agonist, was able to block its effects; however, hexamethonium, a peripherally restricted nonselective nicotinic antagonist, was able to block nicotine's effect on stretching behaviour but not on CPA. In addition, systemic administration of α7 nAChR full agonists PHA543613 and PNU282987 was failed to block stretching and CPA behaviour induced by AA. However, the α7 nAChR-positive allosteric modulator PNU120596 blocked AA-induced CPA in a dose-dependent manner without reducing stretching behaviours. CONCLUSIONS: Our data revealed that while nonselective nAChR activation induces antinociceptive properties on the sensorial and affective signs of visceral pain in mice, α7 nAChRS activation has no effect on these responses. In addition, nonselective nAChR activation-induced antinociceptive effect on stretching behaviour was mediated by central and peripheral mechanisms. However, the effect of nonselective nAChR activation on CPA was mediated centrally. Furthermore, our data suggest a pivotal role of allosteric modulation of α7 nAChRS in the negative affective, but not sensory, component of visceral pain. SIGNIFICANCE: The present results suggest that allosteric modulation of α7 nAChR may provide new strategies in affective aspects of nociception.
BACKGROUND: Preclinical assays of affective and sensorial aspects of nociception play a key role in research on both the neurobiology of pain and the development of novel analgesics. Therefore, we investigated the effects of nicotine and alpha-7 nicotinic acetylcholine receptor (nAChR) modulators in the negative affective and sensory components of visceral pain in mice. METHODS AND RESULTS: Intraperitoneal acetic acid (AA) administration resulted in a robust stretching behaviour and conditioned place aversion (CPA) in mice. We observed a dose-dependent reduction in AA-induced stretching and CPA by the nonselective nAChRs agonist nicotine. Mecamylamine, a nonselective nAChRs agonist, was able to block its effects; however, hexamethonium, a peripherally restricted nonselective nicotinic antagonist, was able to block nicotine's effect on stretching behaviour but not on CPA. In addition, systemic administration of α7 nAChR full agonists PHA543613 and PNU282987 was failed to block stretching and CPA behaviour induced by AA. However, the α7 nAChR-positive allosteric modulator PNU120596 blocked AA-induced CPA in a dose-dependent manner without reducing stretching behaviours. CONCLUSIONS: Our data revealed that while nonselective nAChR activation induces antinociceptive properties on the sensorial and affective signs of visceral pain in mice, α7 nAChRS activation has no effect on these responses. In addition, nonselective nAChR activation-induced antinociceptive effect on stretching behaviour was mediated by central and peripheral mechanisms. However, the effect of nonselective nAChR activation on CPA was mediated centrally. Furthermore, our data suggest a pivotal role of allosteric modulation of α7 nAChRS in the negative affective, but not sensory, component of visceral pain. SIGNIFICANCE: The present results suggest that allosteric modulation of α7 nAChR may provide new strategies in affective aspects of nociception.
Authors: Harumi Kitagawa; Toshiharu Takenouchi; Ryotaro Azuma; Keith A Wesnes; William G Kramer; Donald E Clody; Angela L Burnett Journal: Neuropsychopharmacology Date: 2002-07-11 Impact factor: 7.853
Authors: Patrick M Callahan; Elizabeth J Hutchings; Nancy J Kille; James M Chapman; Alvin V Terry Journal: Neuropharmacology Date: 2012-11-17 Impact factor: 5.250
Authors: Deniz Bagdas; Pretal P Muldoon; Shakir AlSharari; F Ivy Carroll; S Stevens Negus; M Imad Damaj Journal: Neuropharmacology Date: 2015-11-27 Impact factor: 5.250
Authors: S Pons; L Fattore; G Cossu; S Tolu; E Porcu; J M McIntosh; J P Changeux; U Maskos; W Fratta Journal: J Neurosci Date: 2008-11-19 Impact factor: 6.167
Authors: S Stevens Negus; Ember M Morrissey; Marisa Rosenberg; K Cheng; Kenner C Rice Journal: Psychopharmacology (Berl) Date: 2010-01-26 Impact factor: 4.530