Reply to Zhuang et al.: Potential side effects of positive allosteric modulators of the mu-opioid receptor

I appreciate the recent comments by Zhuang et al. (1) on our report. The aim of our work (2) was to establish proof of concept that a positive allosteric modulator (PAM) of the mu-opioid receptor (MOR) affords antinociception in mice by amplifying the activity of opioid peptides acting at MOR. For the PAM to be active, endogenous opioid peptide release is required. We also show that in naive animals the PAM does not cause constipation or a conditioned place preference, indicating a lack of rewarding properties, and only inhibits respiration minimally compared to an equivalent dose of morphine.

In their letter, Zhuang et al. point out the need to investigate the side-effect profile of the PAM in pathological pain models because of the relationship between the sensory and emotional aspects of pain (1). We fully concur with this suggestion; indeed, the small respiratory-depressant effect of the PAM we report in our paper is naloxone-reversible, suggesting a role for released endogenous opioids. Consequently, we conclude in the paper that the early preclinical data are promising enough to move forward with further evaluation of side effects. Few studies evaluate the rewarding effects or other side effects of novel opioids in subjects experiencing chronic pain. However, we agree that this is important based on the mode of action of the MOR PAM. Such studies are ongoing and we are optimistic that the differential spatial and temporal release of peptides across brain regions will provide selectivity of action for the PAM, which is only effective when the orthosteric site of MOR is occupied (3). In addition, the global increase in opioid peptide levels with enkephalinase inhibitors does not produce a conditioned place preference (4) or cause constipation (5) or respiratory depression (6).

A second point raised by Zhuang et al. (1) is that opioid peptides are released into inflamed tissues from immune cells and that these peptides possess unique functional selectivity toward different opioid receptors and may also bias downstream signaling. These statements are true. The PAM-mediated enhancement of the activity of opioid peptides released at inflammatory sites could give site-specific analgesia and may contribute to the peripheral opioid-like side effects (e.g., constipation). However, this enhancement is unlikely to contribute to the serious centrally mediated effects of reward and respiratory depression. We also agree that a MOR PAM could alter the physiology of the opioid system by favoring the action of released peptides at MOR, over the delta-opioid receptor (DOR) or kappa-opioid receptor (KOR). On the other hand, enhanced activation at MOR is necessary to promote analgesia, while increasing activity at other receptors could increase off-target side effects; e.g., excessive DOR activation could be proconvulsant (7) and excessive KOR activation could lead to depressive and aversive behaviors (8). Alteration of signaling bias is seen with allosteric modulators at other G-protein-coupled receptors, and we would expect to see this at MOR, as discussed in our report.

Overall, we look forward to experimentally answering the questions raised in the letter by Zhuang et al. (1).