Findings May Have Clinical Significance in Overcoming Opioid Tolerance and Dependence

A new study published March 24 in Cell Reports found that stimulation of the inflammatory pain-associated neurokinin 1 receptor (NK1R) pathway by substance P alters the phosphorylation state of the mu-opioid receptor (MOR), and that this crosstalk between pain and opioid analgesia increased the rate at which opioid receptors were delivered back to the cell surface, thereby enhancing the cell’s re-sensitization to opioid signaling.  The research was led by Manojkumar Puthenveedu, PhD, assistant professor, biological sciences, Carnegie Mellon University, Pittsburgh. Macdonald Christie, professor of pharmacology, University of Sydney, Australia, studies opioid receptor pharmacology but was not involved with the current research. Commenting on the findings, he said they strongly suggest that “if we can actually target or accelerate endosomal recycling of opiate receptors … then we might be able to restore responsiveness at the receptor more effectively and overcome tolerance, one of the big problems of opiate therapeutics.”

Many different opioid agonists have been derived from morphine, and they all have the same problems, noted Dr. Puthenveedu. If they are effective against pain, generally they also cause tolerance and dependence, and it has been difficult to separate out these adverse effects from the beneficial impact on pain, partly because efforts have largely focused on modifying the agonist itself in order to change the signaling behavior of the receptor. Puthenveedu stated that this study suggests that it may be possible instead to change the events that occur after the receptor binds to the agonist, thereby affecting the physiological response to the opioid. More detail about the research findings may be read here.

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