Bagdas D, Meade J A, Alkhlaif Y, Muldoon P P, Carroll F I, Damaj M I
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
The Center for the Study for Tobacco Products, Virginia Commonwealth University, Richmond, USA.
Eur J Pain. 2018 Apr 10. doi: 10.1002/ejp.1231.
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.
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.
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.
The present results suggest that allosteric modulation of α7 nAChR may provide new strategies in affective aspects of nociception.
伤害性感受的情感和感觉方面的临床前测定在疼痛神经生物学研究和新型镇痛药开发中都起着关键作用。因此，我们研究了尼古丁和α-7烟碱型乙酰胆碱受体（nAChR）调节剂对小鼠内脏痛的负面情感和感觉成分的影响。
腹腔注射醋酸（AA）可导致小鼠出现强烈的伸展行为和条件性位置厌恶（CPA）。我们观察到非选择性nAChRs激动剂尼古丁可使AA诱导的伸展和CPA呈剂量依赖性降低。非选择性nAChRs拮抗剂美加明能够阻断其作用；然而，外周受限的非选择性烟碱拮抗剂六甲铵能够阻断尼古丁对伸展行为的作用，但不能阻断其对CPA的作用。此外，全身给予α7 nAChR完全激动剂PHA543613和PNU282987未能阻断AA诱导的伸展和CPA行为。然而，α7 nAChR正向变构调节剂PNU120596以剂量依赖性方式阻断了AA诱导的CPA，而不降低伸展行为。
我们的数据显示，虽然非选择性nAChR激活可诱导对小鼠内脏痛的感觉和情感体征的抗伤害感受特性，但α7 nAChRs激活对这些反应没有影响。此外，非选择性nAChR激活诱导的对伸展行为的抗伤害感受作用由中枢和外周机制介导。然而，非选择性nAChR激活对CPA的作用由中枢介导。此外，我们的数据表明α7 nAChRs的变构调节在内脏痛的负面情感而非感觉成分中起关键作用。
目前的结果表明，α7 nAChR的变构调节可能为伤害感受的情感方面提供新的策略。
