Chronic morphine regulates TRPM8 channels via MOR-PKC\u03b2 signaling

Lilian Basso,Manon Defaye,Rithwik Ramachandran,Corinne Roland,Mircea Iftinca,Tuan Trang,Christophe Altier,Ahmed Hassan,Robyn Flynn,Charlie Kwok

doi:10.1186/s13041-020-00599-0

Lilian Basso, Manon Defaye + Show 8 more

Open Access

https://doi.org/10.1186/s13041-020-00599-0

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Abstract

Postoperative shivering and cold hypersensitivity are major side effects of acute and chronic opioid treatments respectively. TRPM8 is a cold and menthol-sensitive channel found in a subset of dorsal root ganglion (DRG) nociceptors. Deletion or inhibition of the TRPM8 channel was found to prevent the cold hyperalgesia induced by chronic administration of morphine. Here, we examined the mechanisms by which morphine was able to promote cold hypersensitivity in DRG neurons and transfected HEK cells. Mice daily injected with morphine for 5 days developed cold hyperalgesia. Treatment with morphine did not alter the expressions of cold sensitive TREK-1, TRAAK and TRPM8 in DRGs. However, TRPM8-expressing DRG neurons isolated from morphine-treated mice exhibited hyperexcitability. Sustained morphine treatment in vitro sensitized TRPM8 responsiveness to cold or menthol and reduced activation-evoked desensitization of the channel. Blocking phospholipase C (PLC) as well as protein kinase C beta (PKCβ), but not protein kinase A (PKA) or Rho-associated protein kinase (ROCK), restored channel desensitization. Identification of two PKC phosphorylation consensus sites, S1040 and S1041, in the TRPM8 and their site-directed mutation were able to prevent the MOR-induced reduction in TRPM8 desensitization. Our results show that activation of MOR by morphine 1) promotes hyperexcitability of TRPM8-expressing neurons and 2) induces a PKCβ-mediated reduction of TRPM8 desensitization. This MOR-PKCβ dependent modulation of TRPM8 may underlie the onset of cold hyperalgesia caused by repeated administration of morphine. Our findings point to TRPM8 channel and PKCβ as important targets for opioid-induced cold hypersensitivity.

Highlights

Opioids are widely used analgesics for the treatment of moderate to severe pain but their use often leads to the development of severe side effects, including opioid induced cold hyperalgesia [1,2,3]
Chronic morphine treatment induces cold hypersensitivity and enhances the excitability of TRPM8-expressing neurons To determine whether morphine treatment could modulate cold sensitivity, we used a behavioral paradigm in which cold response latencies were assessed on the first and fifth day of morphine injection [22]
We report that morphine-induced cold hyperalgesia in mice is associated with 1) an increase in neuronal excitability of TRPM8-expressing Dorsal root ganglia (DRG) neurons and 2) a loss of TRPM8 desensitization evoked by cold or menthol

Summary

Introduction

Opioids are widely used analgesics for the treatment of moderate to severe pain but their use often leads to the development of severe side effects, including opioid induced cold hyperalgesia [1,2,3]. MOR activates Gαi/o proteins leading to inhibition of cyclic adenosine. Cold hyperalgesia can appear in diseased states such as complex regional pain syndrome, diabetic neuropathy or Iftinca et al Molecular Brain (2020) 13:61 chronic nerve injury [8]. Change in cold perception is a common manifestation of chronic morphine administration and associated withdrawal syndromes [1, 9]. TRPM8 is activated by chemical cooling agents such as menthol, but inhibited by inflammatory agents [13, 14]. TRPM8 knockout mice show impaired cold sensation, cold allodynia, and analgesia, demonstrating the role of TRPM8 in cold sensation [15,16,17]

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