Effects of facilitated desensitization of µ-opioid receptors on analgesic and respiratory depressive tolerance development in vivo

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Opioids are the most effective drugs for treating severe pain, but their long-term clinical use is limited by the development of analgesic tolerance and dependence. Curiously, other opioid effects such as respiratory depression or constipation develop little or no tolerance. The first and most critical biochemical step in tolerance development is agonist-induced phosphorylation of the C-terminal Ser/Thr residues of the µ-opioid receptor (MOP), leading to desensitization of the receptor. Using a newly developed technique to visualize phosphorylated MOP receptors in the brain, we made the unexpected observation that MOP phosphorylation does not occur ubiquitously after opioid exposure. In fact, a significant mismatch between MOP expression and phosphorylation was found, with detectable MOP phosphorylation strikingly low in some brain regions particularly rich in MOP expression, such as the nucleus accumbens and striatum. This led to the hypothesis of "lack of kinases" in these brain regions, particularly G protein-coupled receptor kinases (GRK). We hypothesize that limited tolerance development in respiratory depression or constipation may be due to a failure of MOP desensitization because of the lack of co-expression of GRKs. To test this hypothesis, we propose to generate mouse models that co-express endogenous MOP receptors with either GRK2 or GRK5, which are known to contribute in different ways to MOP phosphorylation induced by high- or low-efficacy opioids. We hypothesize that in these mice, all MOP receptors will undergo agonist-induced phosphorylation and thus desensitization, leading to increased tolerance not only to analgesic effects but also to respiratory depression and constipation after repeated opioid exposure. It is also possible that facilitated MOP desensitization reduces the addictive properties of opioids in these mice. Increased tolerance to analgesic and respiratory depressant effects of opioids would be clinically desirable, as opioid dose escalation would not be limited by potentially fatal respiratory arrest. The proposed project aims to provide important data to support such a clinical strategy and may stimulate the exploration of drugs that modulate GRK expression or activity as a novel therapeutic concept.