Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States.
Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, United States.
Pain. 2018 Aug;159(8):1607-1620. doi: 10.1097/j.pain.0000000000001247.
The latent sensitization model of chronic pain reveals that recovery from some types of long-term hyperalgesia is an altered state in which nociceptive sensitization persists but is suppressed by the ongoing activity of analgesic receptors such as μ-opioid receptors (MORs). To determine whether these MORs are the ones present in nociceptive afferents, we bred mice expressing Cre-recombinase under the Nav1.8 channel promoter (Nav1.8cre) with MOR-floxed mice (flMOR). These Nav1.8cre/flMOR mice had reduced MOR expression in primary afferents, as revealed by quantitative PCR, in situ hybridization, and immunofluorescence colocalization with the neuropeptide calcitonin gene-related peptide. We then studied the recovery from chronic pain of these mice and their flMOR littermates. When Nav1.8cre/flMOR mice were injected in the paw with complete Freund adjuvant they developed mechanical hyperalgesia that persisted for more than 2 months, whereas the responses of flMOR mice returned to baseline after 3 weeks. We then used the inverse agonist naltrexone to assess ongoing MOR activity. Naltrexone produced a robust reinstatement of hyperalgesia in control flMOR mice, but produced no effect in the Nav1.8/flMOR males and a weak reinstatement of hyperalgesia in Nav1.8/flMOR females. Naltrexone also reinstated swelling of the hind paw in flMOR mice and female Nav1.8cre/flMOR mice, but not male Nav1.8cre/flMOR mice. The MOR agonist DAMGO inhibited substance P release in flMOR mice but not Nav1.8cre/flMOR mice, demonstrating a loss of MOR function at the central terminals of primary afferents. We conclude that MORs in nociceptive afferents mediate an ongoing suppression of hyperalgesia to produce remission from chronic pain.
慢性疼痛的潜伏致敏模型表明，某些类型的长期痛觉过敏的恢复是一种改变的状态，其中伤害感受敏化持续存在，但被镇痛受体（如μ-阿片受体（MOR））的持续活动所抑制。为了确定这些 MOR 是否是伤害感受器中的那些，我们通过 Nav1.8 通道启动子（Nav1.8cre）在 MOR 基因敲除（flMOR）小鼠中表达 Cre 重组酶。这些 Nav1.8cre/flMOR 小鼠的初级传入纤维中 MOR 表达减少，这通过定量 PCR、原位杂交和与神经肽降钙素基因相关肽的免疫荧光共定位显示。然后，我们研究了这些小鼠及其 flMOR 同窝仔鼠从慢性疼痛中恢复的情况。当 Nav1.8cre/flMOR 小鼠在爪子中注射完全弗氏佐剂时，它们会发展出持续超过 2 个月的机械性痛觉过敏，而 flMOR 小鼠的反应在 3 周后恢复到基线。然后，我们使用反向激动剂纳曲酮来评估持续的 MOR 活性。纳曲酮在对照 flMOR 小鼠中产生了强烈的痛觉过敏再发，但在 Nav1.8/flMOR 雄性小鼠中没有作用，在 Nav1.8/flMOR 雌性小鼠中产生了较弱的痛觉过敏再发。纳曲酮还使 flMOR 小鼠和雌性 Nav1.8cre/flMOR 小鼠的后爪肿胀恢复，但不能使 Nav1.8cre/flMOR 雄性小鼠的肿胀恢复。MOR 激动剂 DAMGO 抑制了 flMOR 小鼠中的 P 物质释放，但不能抑制 Nav1.8cre/flMOR 小鼠中的释放，这表明初级传入纤维的中枢末端的 MOR 功能丧失。我们的结论是，伤害感受器中的 MOR 介导了对痛觉过敏的持续抑制，从而产生慢性疼痛的缓解。
