Mu-Opioid Receptor (MOR) Dependence of Pain in Chemotherapy-Induced Peripheral Neuropathy.

Abstract

We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared to inflammatory, pain, the crosstalk between nociceptor TLR4 and mu-opioid receptors (MOR), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether: i ) antisense knockdown of nociceptor MOR attenuates CIPN, ii ) and attenuates the priming associated with CIPN, and iii ) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin induced-priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming (the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)), a MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain.Significance Statement It remains unknown why opioid analgesics are less effective against neuropathic pain, including that induced by cancer chemotherapy. Here we demonstrate a crucial role of nociceptor mu-opioid receptors (MOR) in chemotherapy-induced peripheral neuropathy (CIPN) pain and hyperalgesic priming (priming), the latter a mechanism involved in the transition from acute to chronic pain. In addition to neuropathic pain and priming, opioid-induced hyperalgesia (OIH) also develops in chemotherapy-treated rats, which is reversed by inhibitors of second messengers that also reverse Type II priming, as well as by MOR and TLR4 antagonists. Taken together our results support the suggestion that priming and OIH contribute to CIPN and its limited responsiveness to opioid analgesics.