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.

Chronic morphine regulates TRPM8 channels via MOR-PKCβ signaling

“…Shapovalov et al found a distinct mechanism of TRPM8 regulation in rat DRG neurons with morphine administration leading to an increase in TRPM8 internalization [18]. In contrast to what was reported by Gong et al [19] we did not observe an increase in TRPM8 mRNA expression in response to morphine. In addition, assessment of plasma membrane biotinylated fraction did not reveal an alteration in TRPM8 surface expression.…”

“…The activity of the thermosensor TRPM8 in primary sensory neurons is unique in that it senses cool temperatures but also mediates cold-induced analgesia [10][11][12]. TRPM8 was previously found to be involved in the development of cold hyperalgesia following chronic morphine administration, although the underlying mechanisms of this effect involved an upregulation of the channel expression [19]. Shapovalov et al found a distinct mechanism of TRPM8 regulation in rat DRG neurons with morphine administration leading to an increase in TRPM8 internalization [18].…”

“…A functional link between MOR and TRPM8 has been suggested to support the well-recognized opioid-induced modulation of thermosensation, but results are conflicting [18]. Whereas some authors have shown that prolonged MOR stimulation leads to the internalization of TRPM8 thereby causing morphine-induced cold analgesia [18], others have observed that chronic administration of morphine could lead to an upregulation of TRPM8 expression in sensory neurons [19]. Here, we examined the signaling pathway(s) linking MOR to TRPM8, using behavioral, electrophysiological and biochemical assessment of TRPM8 function and expression after chronic morphine treatment.…”

Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

“…Two hours before menthol administration, rats were subjected to an intraperitoneal administration of a selective TRPM8 antagonist RQ-00203078 (purchased from Tocris Biosicence, United Kingdom) at 0, 0.3, and 3 mg/kg (dissolved in DMSO and then diluted with deionized water) in a within-subject Latin square design. These dose were selected based on the fact that in rats the ED50 value of RQ-00203078 via oral administration is 0.65 mg/kg and that RQ-00203078 at 3 mg/kg dose via intraperitoneal administration produced a profound TRPM8-blocking effect (Gong and Jasmin, 2017; Ohmi et a., 2014). To guarantee the extinction baseline before each test sessions, two extinction sessions were conducted between test sessions.…”

Regulation of TRPM8 channels by PKCβ mediates morphine-induced cold hypersensitivity.

“…We also found that prolonged activation of MOR by The activity of the thermosensor TRPM8 in primary sensory neurons is unique in that it senses cool temperatures but also mediates cold-induced analgesia 10−12 . TRPM8 was previously found to be involved in the development of cold hyperalgesia following chronic morphine administration, although the underlying mechanisms of this effect involved an upregulation of the channel expression 19 .…”