Sustained morphine administration induces TRPM8 dependent cold hyperalgesia

Abstract

It is not uncommon for patients chronically treated with opioids to exhibit opioid induced hyperalgesia (OIH), and this has been widely reported both clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate (NMDA) receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in OIH. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels both by patch clamp recording on sensory neurons and western blot on dorsal root ganglia (DRGs). The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine treated rats. Also, TRPM8 knockout mice (KO) failed to develop cold hyperalgesia after chronic administration of morphine. Our results demonstrate that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization.

Perspective

Patients receiving chronic opioid are sensitive to cold. We now show in mice and rats that sustained morphine administration induces cold hyperalgesia and an up-regulation of TRPM8. Knockout or selectively blocking TRPM8 reduces morphine induced cold hyperalgesia suggesting TRPM8 is regulated by opioids.