Cargando…

Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats

Neuronal nicotinic acetylcholine receptor (nAChR)-based therapeutics are sought as a potential alternative strategy to opioids for pain management. In this study, we examine the antinociceptive effects of 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoxazole (CMPI), a novel pos...

Descripción completa

Detalles Bibliográficos
Autores principales: Deba, Farah, Ramos, Kara, Vannoy, Matthew, Munoz, Kemburli, Akinola, Lois S., Damaj, M. Imad, Hamouda, Ayman K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355939/
https://www.ncbi.nlm.nih.gov/pubmed/32630476
http://dx.doi.org/10.3390/molecules25122923
_version_ 1783558391618076672
author Deba, Farah
Ramos, Kara
Vannoy, Matthew
Munoz, Kemburli
Akinola, Lois S.
Damaj, M. Imad
Hamouda, Ayman K.
author_facet Deba, Farah
Ramos, Kara
Vannoy, Matthew
Munoz, Kemburli
Akinola, Lois S.
Damaj, M. Imad
Hamouda, Ayman K.
author_sort Deba, Farah
collection PubMed
description Neuronal nicotinic acetylcholine receptor (nAChR)-based therapeutics are sought as a potential alternative strategy to opioids for pain management. In this study, we examine the antinociceptive effects of 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoxazole (CMPI), a novel positive allosteric modulator (PAM), with preferential selectivity to the low agonist sensitivity (α4)3(β2)2 nAChR and desformylflustrabromine (dFBr), a PAM for α4-containing nAChRs. We used hot plate and tail flick tests to measure the effect of dFBr and CMPI on the latency to acute thermal nociceptive responses in rats. Intraperitoneal injection of dFBr, but not CMPI, dose-dependently increased latency in the hot plate test. In the tail flick test, the effect achieved at the highest dFBr or CMPI dose tested was only <20% of the maximum possible effects reported for nicotine and other nicotinic agonists. Moreover, the coadministration of dFBr did not enhance the antinociceptive effect of a low dose of nicotine. Our results show that the direct acute effect of dFBr is superior to that for CMPI, indicating that selectivity to (α4)3(β2)2 nAChR is not advantageous in alleviating responses to acute thermal nociceptive stimulus. However, further studies are necessary to test the suitability of (α4)3(β2)2 nAChR-selective PAMs in chronic pain models.
format Online
Article
Text
id pubmed-7355939
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-73559392020-07-22 Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats Deba, Farah Ramos, Kara Vannoy, Matthew Munoz, Kemburli Akinola, Lois S. Damaj, M. Imad Hamouda, Ayman K. Molecules Article Neuronal nicotinic acetylcholine receptor (nAChR)-based therapeutics are sought as a potential alternative strategy to opioids for pain management. In this study, we examine the antinociceptive effects of 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoxazole (CMPI), a novel positive allosteric modulator (PAM), with preferential selectivity to the low agonist sensitivity (α4)3(β2)2 nAChR and desformylflustrabromine (dFBr), a PAM for α4-containing nAChRs. We used hot plate and tail flick tests to measure the effect of dFBr and CMPI on the latency to acute thermal nociceptive responses in rats. Intraperitoneal injection of dFBr, but not CMPI, dose-dependently increased latency in the hot plate test. In the tail flick test, the effect achieved at the highest dFBr or CMPI dose tested was only <20% of the maximum possible effects reported for nicotine and other nicotinic agonists. Moreover, the coadministration of dFBr did not enhance the antinociceptive effect of a low dose of nicotine. Our results show that the direct acute effect of dFBr is superior to that for CMPI, indicating that selectivity to (α4)3(β2)2 nAChR is not advantageous in alleviating responses to acute thermal nociceptive stimulus. However, further studies are necessary to test the suitability of (α4)3(β2)2 nAChR-selective PAMs in chronic pain models. MDPI 2020-06-25 /pmc/articles/PMC7355939/ /pubmed/32630476 http://dx.doi.org/10.3390/molecules25122923 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Deba, Farah
Ramos, Kara
Vannoy, Matthew
Munoz, Kemburli
Akinola, Lois S.
Damaj, M. Imad
Hamouda, Ayman K.
Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats
title Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats
title_full Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats
title_fullStr Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats
title_full_unstemmed Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats
title_short Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats
title_sort examining the effects of (α4)3(β2)2 nicotinic acetylcholine receptor-selective positive allosteric modulator on acute thermal nociception in rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355939/
https://www.ncbi.nlm.nih.gov/pubmed/32630476
http://dx.doi.org/10.3390/molecules25122923
work_keys_str_mv AT debafarah examiningtheeffectsofa43b22nicotinicacetylcholinereceptorselectivepositiveallostericmodulatoronacutethermalnociceptioninrats
AT ramoskara examiningtheeffectsofa43b22nicotinicacetylcholinereceptorselectivepositiveallostericmodulatoronacutethermalnociceptioninrats
AT vannoymatthew examiningtheeffectsofa43b22nicotinicacetylcholinereceptorselectivepositiveallostericmodulatoronacutethermalnociceptioninrats
AT munozkemburli examiningtheeffectsofa43b22nicotinicacetylcholinereceptorselectivepositiveallostericmodulatoronacutethermalnociceptioninrats
AT akinolaloiss examiningtheeffectsofa43b22nicotinicacetylcholinereceptorselectivepositiveallostericmodulatoronacutethermalnociceptioninrats
AT damajmimad examiningtheeffectsofa43b22nicotinicacetylcholinereceptorselectivepositiveallostericmodulatoronacutethermalnociceptioninrats
AT hamoudaaymank examiningtheeffectsofa43b22nicotinicacetylcholinereceptorselectivepositiveallostericmodulatoronacutethermalnociceptioninrats