Nociceptor Neuroplasticity Associated with Opioid-Induced Hyperalgesia.

Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, , subcutaneous administration of an analgesic dose of fentanyl (30 μg/kg, s.c.) was performed in male rats. Two days later, when fentanyl was administered intradermally (1 μg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E (PGE) hyperalgesia. OIH was reversed, , by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nm) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a μ-opioid receptor (MOR)-dependent increase in [Ca] in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4 and IB4 neurons. This sensitizing effect of fentanyl was reversed in weakly IB4 DRG neurons cultured from opioid-primed rats after treatment with cordycepin, to reverse of OIH. Thus, administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH. Clinically used μ-opioid receptor agonists such as fentanyl can produce hyperalgesia and hyperalgesic priming. We report on an model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid-naive and opioid-primed animals, and provide evidence for the important role of nociceptor μ-opioid receptor-mediated calcium signaling and peripheral protein translation in the weakly IB4-binding population of nociceptors in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.