The Peripheral Opioid Receptor as a Therapeutic Target

Researchers discuss why peripheral opioid receptors are normally inactive.

Opioids are highly effective analgesics prescribed to treat a variety of acute and chronic pain conditions. The most commonly used opioids target the µ-opioid receptors (MORs) and mediate their analgesic effects primarily through the central nervous system (CNS).

In the quest for safer ways to manage chronic pain, researchers are increasingly looking to peripheral opioid receptors as potential therapeutic targets.

In a symposium at the 35th Annual Scientific Meeting of the American Pain Society, Dr Nathan Jeske, Associate Professor at the University of Texas Health Science Center, San Antonio, Texas, explained that effective targeting of peripheral opioid receptors would produce analgesia without adverse CNS-mediated effects.

In an interview with Clinical Pain Advisor, Dr Jeske said the challenge with this approach is that “peripheral opioid receptors exist in a constitutively inactive state as far as the potential of analgesic action is concerned.” In other words, peripheral opioid receptors are “analgesically incompetent.” At the symposium, Dr Jeske discussed what his research team discovered about why peripheral opioid receptors are normally inactive.

The team’s findings expand on the previously identified constitutive association between G protein-coupled receptor kinase 2 (GRK2) and the plasma membrane δ-opioid receptors (DOR) in peripheral sensory neurons.

In preclinical experiments, Dr Jeske and associates found that GRK2 downregulates DOR activity in the periphery, inhibiting DOR responsiveness to opioids.2 They also discovered that activating bradykinin receptors in sensory neurons caused GRK2 to migrate away from DOR in the plasma membrane and toward Raf kinase inhibitory protein (RKIP), a cytosolic scaffolding protein. Retention of GRK2 in the cytosol resulted in the restoration of DOR activity in sensory neurons, which has important clinical implications.2

“Clinically, preventing constitutive GRK2 association with DOR would increase peripheral DOR responses to not only endogenous [opioid] agonists but also to administered [opioid] agonists, thereby increasing analgesia while reducing negative, systemic side effects,” Dr Jeske said. Their findings are supported by other studies, which he said have shown that “systemic opioid analgesia can be recapitulated with up to 60% efficacy by activing just peripheral opioid receptors.”

Bradykinin is a strong mediator of inflammation, and the observation by Dr Jeske and colleagues that bradykinin receptor activation might be a catalyst for restoring DOR functionality is consistent with previously published reports of inflammation-induced activation of peripheral opioid receptors.3 During inflammation, expression and transport of peripheral opioid receptors increase. Accumulation of peripheral opioid receptors on the peripheral terminals of sensory nerves promotes an enhanced response to endogenous and administered agonists.3

If further studies uphold the findings, which Dr Jeske said have been submitted for publication, the eventual goal would be to develop a pharmaceutical able to target the mechanism his team identified for sequestering GRK2.

“If we can make peripheral opioid receptors more receptive to agonist activation, we can provide analgesic effects with localized treatments that will subsequently reduce the potential for addiction, tolerance, and respiratory depression,” Dr Jeske concluded.


  1. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115:1363-1381.
  2. Jeske N. Priming peripheral opioid receptors involves blocking constitutive desensitization. Presented at: 35th Annual Scientific Meeting of the American Pain Society. May 11-14, 2016; Austin, Texas.
  3. Sehgal N, Smith HS, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician. 2011;14:249-258.