Mischel Ryan A, Dewey William L, Akbarali Hamid I
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 E. Clay St., McGuire Hall 100D, Richmond, VA 23298, USA.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 E. Clay St., McGuire Hall 100D, Richmond, VA 23298, USA.
iScience. 2018 Apr 27;2:193-209. doi: 10.1016/j.isci.2018.03.003.
In the clinical setting, analgesic tolerance is a primary driver of diminished pain control and opioid dose escalations. Integral to this process are primary afferent sensory neurons, the first-order components of nociceptive sensation. Here, we characterize the factors modulating morphine action and tolerance in mouse small diameter dorsal root ganglia (DRG) neurons. We demonstrate that acute morphine inactivates tetrodotoxin-resistant (TTX-R) Na channels in these cells. Chronic exposure resulted in tolerance to this effect, which was prevented by treatment with oral vancomycin. Using colonic supernatants, we further show that mediators in the gut microenvironment of mice with chronic morphine exposure can induce tolerance and hyperexcitability in naive DRG neurons. Tolerance (but not hyperexcitability) in this paradigm was mitigated by oral vancomycin treatment. These findings collectively suggest that gastrointestinal microbiota modulate the development of morphine tolerance (but not hyperexcitability) in nociceptive primary afferent neurons, through a mechanism involving TTX-R Na channels.
在临床环境中，镇痛耐受性是疼痛控制减弱和阿片类药物剂量增加的主要驱动因素。伤害性感觉的一级组成部分——初级传入感觉神经元是这一过程的核心。在此，我们描述了调节小鼠小直径背根神经节（DRG）神经元中吗啡作用和耐受性的因素。我们证明，急性吗啡可使这些细胞中的河豚毒素抗性（TTX-R）钠通道失活。长期暴露导致对这种效应产生耐受性，口服万古霉素治疗可预防这种耐受性。使用结肠上清液，我们进一步表明，慢性吗啡暴露小鼠肠道微环境中的介质可诱导未接触过药物的DRG神经元产生耐受性和兴奋性过高。在这种模式下，口服万古霉素治疗可减轻耐受性（但不能减轻兴奋性过高）。这些发现共同表明，胃肠道微生物群通过一种涉及TTX-R钠通道的机制调节伤害性初级传入神经元中吗啡耐受性（而非兴奋性过高）的发展。
