There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia
and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate
to severe pain, and their efficacy in the alleviation of pain is well recognized.
Unfortunately, chronic treatment with opioid analgesics induces central analgesic
tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms,
including receptor desensitization, G-protein decoupling, β-arrestin recruitment,
and alterations in the expression of peripheral MORs and microbiota have been postulated
to contribute to the development of opioid analgesic tolerance. However, these studies
are largely focused on central opioid analgesia and tolerance. Accumulated literature
supports that peripheral MORs mediate analgesia, but controversial results on the
development of peripheral opioid receptors-mediated analgesic tolerance are reported.
In this review, we offer evidence on the consequence of the activation of peripheral
MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic
efficacy and decrease the development of tolerance to opioids at the peripheral sites.
We have also addressed the advantages and drawbacks of the activation of peripheral
MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central
and peripheral analgesic tolerance.
