TREK ion channels, targets involved in pathophysiology and pharmacology of pain – TREK PAIN

We combine experimental in vitro (fluorescence microscopy, electrophysiology), ex vivo (electrophysiology of sensory nerves) and behavioral approaches. We study the impact of genetic or pharmacological invalidation of these channels on (i) the painful symptoms in animal models of these diseases (ii) the effects of morphine.

The TREK-2 channels are involved in the pathophysiology of inflammatory pain and in cold allodynia induced by oxalipaltin (used for the treatment of colorectal cancers).
TREK-1 channels are involved in the analgesic effect of morphine but not its side effects (constipating effects, respiratory depression, addiction).

A better knowledge of the role of TREK channels in the etiology of pain and the role of TREK-1 channels in the analgesic effect of morphine enhances considerable interest in this channel as a molecular target for the development of new analgesics. The validation of the analgesic potential activators of TREK channels associated with an improved benefit/risk ratio could have major medical improvement in the market of painkillers which is orphan of innovation and is yet constantly growing.

To date, an article is in revision. Deviliers, et al., TREK-1 dissociates from opposing analgesic effects of morphine
A second article is being submitted: Pereira et al., The mechanical-, thermal-and lipid-sensing K + channel TREK2 tunes mechanical-, cool-and warm-temperature perception in physiological and pathophysiological conditions.

Scientific background and rationale.
In spite of the improvement of fundamental knowledge on pathophysiology of pain, limited conceptual progress has been done in its pharmacological management. Most of the reference drugs for nociceptive pain (morphine, acetaminophen, non steroidal anti-inflammatory drugs) or neuropathic pain (antidepressants and antiepileptics) are old or very old. Moreover, their benefit/risk ratio is not optimal due to a limited efficacy for some of them or to adverse effects for others. Published work from the two teams involved in the project has shown that TREK1 and TRAAK channels are involved in perception of nociceptive stimuli in healthy animals. These results justify to perform further studies to assess the involvement of such proteins in pathophysiology of pain. We decide to focus on TREK-1 and TREK-2 channels, the later being poorly studied in this context. Besides, ion channels, among which potassium channels, are effectors of receptors coupled to proteins G. Regarding literature data and preliminary personal results we hypothesize that TREK-1 and TREK -2 channels could be effectors for mu opioid receptors. We plan to determine this relationship and its involvement in the analgesic effect of morphine.
Moreover, other data from the literature suggest that a dissociation between analgesic and adverse effects of morphine may exist. Accordingly, we plan to assess if TREK-1 and TREK-2 would be differentially involved in the analgesic and adverse effects of morphine and if their activation would give the opportunity to induce analgesia without opioid-like adverse effects.
To demonstrate, thanks to this pathophysiological and pharmacological strategy, a double involvement of these channels would increase the relevance of their potential role as targets for pain management.
Description of the project.
Two complementary strategies will be used: 1) Determination of the physiological role of TREK-2 channels in nociception and of the pathophysiological involvement of TREK-1 and TREK-2 in inflammation and post-traumatic and chemotherapy-induced neuropathic pain. We will investigate how genetic deletion of these channels induces pain symptoms, as well as their peripheral and spinal expression and their functionality in the pathological models. 2) Analysis i) of the involvement of these channels in the analgesic effect of morphine ii) of their non involvement in morphine’s adverse effects (e.g. constipation and respiratory depression). This work will need in vivo or ex vivo studies of the effects of opioids in animals or tissues with (or without) TREK expression and in vitro studies for the characterization of the coupling between µ opioid receptors and TREK channels. Study of analgesic and adverse effects of riluzol, a non specific activator of these channels, will permit the validation of the concept that such activators may be novel analgesics. Behavioral, molecular, cellular, electrophysiological (patch-clamp, skin-nerve) methods will be used in wild-type and knock out mice and will benefit from complementary skills of the two teams.
Expected results.
Our published and preliminary results showed that deletion of the TREK-1 and TRAAK potassium channels induced hyperalgesia and that TREK-1 channels might differentially participate to analgesia and constipation induced by morphine.
This project would confirm these preliminary data and give new pieces of information. That will suggest a pathophysiological role of TREK channels in inflammatory and neuropathic pain and lead to consider them as novel targets for pain relief. The demonstration that activation of these channels induces an opioid-like analgesic effect, but not constipation or other adverse effects, will reinforce their interest in analgesia. The new horizons opened by the project will be the synthesis of activators of these channels as novel analgesics.