Opiates Modulate Thermosensation by Internalizing Cold Receptor TRPM8

•Morphine inhibits cold receptor TRPM8 in sensory neurons•TRPM8 cointernalizes with the opioid receptor OPRM1 upon morphine binding•Mouse TRPM8 knockout leads to a decrease in morphine-induced cold analgesia•Withdrawal syndrome induced by naloxone requires TRPM8 presence

SummaryStimulation of μ-opioid receptors (OPRMs) brings powerful pain relief, but it also leads to the development of tolerance and addiction. Ensuing withdrawal in abstinent patients manifests itself with severe symptoms, including cold hyperalgesia, often preventing addicted patients from successfully completing the rehabilitation. Unsurprisingly, OPRMs have been a central point of many studies. Nonetheless, a satisfactory understanding of the pathways leading to distorted sensory responses during opiate administration and abstinence is far from complete. Here, we present a mechanism that leads to modulation by OPRMs of one of the sensory responses, thermosensation. Activation of OPRM1 leads to internalization of a cold-sensor TRPM8, which can be reversed by a follow-up treatment with the inverse OPRM agonist naloxone. Knockout of TRPM8 protein leads to a decrease in morphine-induced cold analgesia. The proposed pathway represents a universal mechanism that is probably shared by regulatory pathways modulating general pain sensation in response to opioid treatment.

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