Opioid-Induced Hyperalgesic Priming in Single Nociceptors

Clinical mu-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E-2 (PGE(2)) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and mitogen-activated protein kinase (MAPK) inhibitors, which reverses Type H priming, both partially attenuated OIHP. Parallel in vitro experiments were performed on small-diameter (<30 mu m) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type H priming. Enhancement of the sensitizing effect of a low concentration of PGE(2) (10 nM), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4-) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE(2) (100 nM) was enhanced. The sensitizing effect of 10 nM PGE(2) was attenuated in weakly IB4+ and IB4- neurons cultured from rats whose OIHP was reversed in vivo. Thus, in vivo administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4- nociceptors that persists in vitro and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nM PGE(2) in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type H priming, remains to be elucidated.