Abstract
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.
Highlights
IntroductionNeuronal nicotinic acetylcholine receptors (nAChRs) containing the α4 and β2 nAChR subunits ( referred to as α4β2* nAChRs with asterisks, to indicate the diversity of subunit composition) are the most predominant nAChR subtypes in the brain [1,2,3]
Neuronal nicotinic acetylcholine receptors containing the α4 and β2 nAChR subunits are the most predominant nAChR subtypes in the brain [1,2,3]
Our results show that the direct acute effect of CMPI on latency to acute thermal stimuli is minimal, and not comparable to that seen with non-selective nAChR agonists, like nicotine, or with positive allosteric modulator (PAM) with broader nAChR subtype coverage, like dFBr
Summary
Neuronal nicotinic acetylcholine receptors (nAChRs) containing the α4 and β2 nAChR subunits ( referred to as α4β2* nAChRs with asterisks, to indicate the diversity of subunit composition) are the most predominant nAChR subtypes in the brain [1,2,3]. The α4β2* nAChRs are expressed in neuronal circuitries involved in the transmission, perception, and modulation of painful stimuli and contribute to the underlying pathophysiological processes of neuropathic and inflammatory pain [4,5,6]. The antinociceptive efficacy of α4β2* nAChRs agonists has been demonstrated in animal models, including those for acute thermal pain, neuropathic pain, pain associated with inflammatory conditions, and chemotherapy-induced painful neuropathy [10,11,12,13]. Molecules 2020, 25, 2923 of clinically relevant nicotinic agonists was proven difficult, despite their potent antinociceptive and anti-inflammatory effects in a variety of preclinical models. Doses of nAChR agonists that produced analgesic effects produced side effects, due to interactions at other nAChRs subtypes (e.g., α3-containing nAChRs) [14,15]. The positive allosteric modulator (PAM) of nAChRs emerged as a class of therapeutic agents to overcome the pharmacological selectivity and safety issues associated with agonists [16,17,18,19,20,21]
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