Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia

Abstract

Opioid pain medications cause detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia, and drive dose escalation. The cell-types and receptors on which opioids act to initiate these maladaptive processes remain disputed, preventing the development of therapies to maximize and sustain opioid analgesic efficacy. Here we establish that mu-opioid receptors (MOR) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA-sequencing and histological analysis revealed that MOR is expressed by nociceptors, but not by spinal microglia. Deletion of MOR specifically in nociceptors eliminated morphine tolerance, OIH, and pronociceptive synaptic long-term potentiation, without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, is sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support combining opioid agonists with peripheral MOR antagonists to limit analgesic tolerance and OIH.

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

“…Those reports confirmed that the biphalin actions we observed are not always related to opioid receptor signaling. Interestingly, the newest results obtained by Corder's group indicated that MOPs are expressed by nociceptors, but not microglia within the spinal cord [84]. Based on those results, our data explained well the strong antinociceptive effects of biphalin after intrathecal injection, since it is known that this opioid can act directly to the nociceptors and indirectly may modulate microglial-derived neuroinflammation in opioid receptor-independent manner.…”

Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

“…However, previous research has implied that the opioid tolerance and opioid-induced hyperalgesia that follow repeated injections of morphine are mediated by primary afferent MORs (55). It was also shown that i.t.…”

“…It was also shown that i.t. morphine produced strong mechanical and thermal antinociception in naive mice but that was lost in mice in which MOR had been deleted only from primary afferents (55) suggesting that spinal neurons expressing mu opiate receptors did not play a role in setting baseline mechanical thresholds or the generation of analgesic tolerance following repeated injections of morphine. However, intrathecal Derm-BOT in the naïve mice reported here, had no effect on baseline mechanical pain sensitivity but only on mechanical thresholds in injury-induced pain states.…”

Therapies and Mechanisms of Opioid Withdrawal

“…Similarly, the clinically available nonselective Panx1 channel blocker probenecid, currently in use as an anti-gout medication, was found to be effective at alleviating opioid withdrawal in rodents [24]. Furthermore, a recent study by Corder et al reported that adverse effects of opioid use may be peripherally mediated [27]. The authors showed that co-delivery of a peripherally restricted opioid antagonist, methylnaltrexone bromide, with morphine produced analgesia without analgesic tolerance and opioid-induced hyperalgesia.…”