The safety and efficacy of opioids are compromised as analgesic tolerance develops. Opioids are also ineffective against neuropathic pain. Recent reports have suggested that inhibitors of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), may have analgesic effects in cancer patients suffering from neuropathic pain. It has been shown that the platelet-derived growth factor receptor-beta (PDGFR-↓), an RTK that has been shown to interact with the EGFR, mediates opioid tolerance but does not induce analgesia. Therefore, we sought to determine whether EGFR signaling was involved in opioid tolerance and if EGFR and PDGFR signaling could induce pain in rats.We found that gefitinib, an EGFR antagonist, eliminated morphine tolerance. In addition, repeated epidermal growth factor (EGF) administration rendered animals unresponsive to subsequent analgesic doses of morphine, a phenomenon we call ‘pre-tolerance’. Using a nerve injury model, we found that gefitinib alone was not analgesic. Rather, it reversed insensitivity to morphine analgesia (‘pre-tolerance’) caused by the release of EGF by injured nerves. We also showed that repeated, but not acute EGF or platelet-derived growth factor-BB (PDGF-BB) administration induced mechanical hypersensitivity in rats. EGFR and PDGFR-↓ signaling interacted to produce this sensitization. EGFR was widely expressed in primary sensory afferent cell bodies, demonstrating a neuroanatomical substrate for our findings.Taken together, our results suggest a direct mechanistic link between opioid tolerance and mechanical sensitization. EGFR antagonism could eventually play an important clinical role in the treatment of opioid tolerance and neuropathic pain that is refractory to opioid treatment. Opioid tolerance and associated reduced effectiveness of opioids against neuropathic pain are two major clinical problems that are prime contributors to the opioid epidemic. However, the mechanisms underlying these phenomena are not clearly understood. Here we show that EGFR antagonism not only blocks morphine tolerance but also restores the effectiveness of opioids against neuropathic pain. Chronic EGF or PDGF administration induces mechanical sensitization, a prominent component of neuropathic pain, and renders animals ‘pre-tolerant’ to subsequent analgesic doses of morphine. Taken together, these results suggest a direct mechanistic link between opioid tolerance and neuropathic pain. EGFR antagonism could eventually play an important role in the treatment of opioid tolerance and severe neuropathic pain that requires ever increasing doses of opioids.Copyright © 2020 Puig et al.
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