Loss of μ-opioid receptor signaling in nociceptors, and not spinal microglia, abrogates morphine tolerance without disrupting analgesic efficacy

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.