Department of Medicine.
Department of Oral and Maxillofacial Surgery.
J Neurosci. 2019 Aug 14;39(33):6414-6424. doi: 10.1523/JNEUROSCI.0966-19.2019. Epub 2019 Jun 17.
In addition to analgesia, opioids produce opioid-induced hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C ε (PKCε) AS-ODN also prevented LDM-induced hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4 and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKCε, HDM-induced analgesia, and priming are neither TLR4 nor PKCε dependent. OIH produced by LDM is mediated by both IB4 and peptidergic nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4 and peptidergic nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed. Opioid-induced hyperalgesia (OIH) and priming are common side effects of opioid agonists such as morphine, which acts at μ-opioid receptors. We demonstrate that OIH and priming induced by systemic low-dose morphine (LDM) share action at Toll-like receptor 4 (TLR4) and signaling via protein kinase C ε (PKCε) in common, whereas systemic high-dose morphine (HDM)-induced analgesia and priming are neither TLR4 nor PKCε dependent. OIH produced by systemic LDM is mediated by isolectin B4-positive (IB4) and peptidergic nociceptors, whereas priming is dependent on a different class of nociceptors. Priming induced by systemic HDM is, however, mediated by both IB4 and peptidergic nociceptors. Our findings may provide useful information for the use of low-dose opioids combined with nonopioid analgesics to treat pain and opioid use disorders.
除了镇痛作用，阿片类药物还会引起阿片类药物诱导的痛觉过敏（OIH）和神经可塑性，表现为炎症介质诱导的痛觉过敏（痛觉过敏启动）延长。我们评估了这样一种假设，即阿片类药物引起的痛觉过敏和启动是由类似的伤害感受器机制介导的。在雄性大鼠中，我们首先评估了伤害感受器 Toll 样受体 4（TLR4）在全身低剂量吗啡（LDM，0.03mg/kg）诱导的 OIH 和启动中的作用。鞘内 TLR4 mRNA 反义寡核苷酸（TLR4 AS-ODN）可预防 LDM 诱导的 OIH 和前列腺素 E 痛觉过敏（启动）的延长。相比之下，高剂量吗啡（HDM，3mg/kg）增加了痛觉阈值（镇痛）并诱导了启动，TLR4 AS-ODN 均不能减轻这两种作用。蛋白激酶 Cε（PKCε）AS-ODN 也可预防 LDM 诱导的痛觉过敏和启动，而 HDM 诱导的镇痛和启动不受影响。用异硫氰酸荧光素 B4（IB4）-蓖麻毒素或 SS 肽-蓖麻毒素（分别耗尽 IB4 和肽能伤害感受器）处理，或两者的组合，可预防全身 LDM 诱导的痛觉过敏，但不能预防启动。在两种蓖麻毒素处理组中，HDM 诱导的启动，但不是镇痛，明显减弱。总之，虽然 LDM 诱导的 OIH 和启动具有共同的受体和第二信使机制，但 TLR4 作用和 PKCε 信号转导，HDM 诱导的镇痛和启动既不是 TLR4 也不是 PKCε 依赖性的。LDM 引起的 OIH 是由 IB4 和肽能伤害感受器共同介导的，而启动则不依赖于同一类伤害感受器。相比之下，HDM 诱导的启动是由 IB4 和肽能伤害感受器共同介导的。讨论了低剂量阿片类药物与非阿片类镇痛药联合使用以及治疗阿片类药物使用障碍的意义。阿片类药物诱导的痛觉过敏（OIH）和启动是阿片类激动剂（如吗啡）的常见副作用，吗啡作用于μ-阿片受体。我们证明，全身低剂量吗啡（LDM）诱导的 OIH 和启动具有共同的 TLR4 作用和 PKCε 信号转导，而全身高剂量吗啡（HDM）诱导的镇痛和启动既不是 TLR4 也不是 PKCε 依赖性的。全身 LDM 引起的 OIH 是由异硫氰酸荧光素 B4（IB4）阳性（IB4）和肽能伤害感受器介导的，而启动则依赖于不同类别的伤害感受器。然而，全身 HDM 诱导的启动是由 IB4 和肽能伤害感受器共同介导的。我们的发现可能为低剂量阿片类药物与非阿片类镇痛药联合治疗疼痛和阿片类药物使用障碍提供有用信息。
