Volume 75, April 2024, 102432Author links open overlay panel, , , Abstract

Chronic pain conditions are unmet medical needs, since the available drugs, opioids, non-steroidal anti-inflammatory/analgesic drugs and adjuvant analgesics do not provide satisfactory therapeutic effect in a great proportion of patients. Therefore, there is an urgent need to find novel targets and novel therapeutic approaches that differ from classical pharmacological receptor antagonism. Most ion channels and receptors involved in pain sensation and processing such as Transient Receptor Potential ion channels, opioid receptors, P2X purinoreceptors and neurokinin 1 receptor are located in the lipid raft regions of the plasma membrane. Targeting the membrane lipid composition and structure by sphingolipid or cholesterol depletion might open future perspectives for the therapy of chronic inflammatory, neuropathic or cancer pain, most importantly acting at the periphery.

Section snippetsAnalgesic targets in the sensory neuronal membrane

Since Transient Receptor Potential (TRP) ion channels especially the TRP Vanilloid 1 (TRPV1) were identified as potential targets for chronic pain [1, 2, 3], great efforts were made in the pharmaceutical industry to develop novel analgesic drugs acting on these receptors. TRPV1 antagonists had considerable preclinical efficacy in relieving both inflammatory and chronic neuropathic pain, and showed effectiveness in postoperative pain, migraine, cancer pain and osteoarthritis models [3, ∗4, 5, 6,

Thermosensitive TRP channels in the focus: TRPV1, Ankyrin 1 (TRPA1), Melastatin 3 and 8 (TRPM3, TRPM8)

TRPV1 was the first discovered receptor of the TRP channel family, and it is still the most studied member. Its activators are vanilloid-type chemical compounds (capsaicin: CAPS, resiniferatoxin: RTX, N-oleoyldopamine: OLDA), lipophilic endogenous compounds (arachidonic acid and its metabolites, eg. anandamide: AEA), other chemical substances, noxious heat (>43 °C) and protons (pH < 5.9). If present together, these stimuli interact with each other [26].

TRPA1 is also well described regarding the

Role of lipid rafts and opioid receptor signaling

ORs, μ (μ-OR), δ (δ-OR), κ (κ-OR) and opioid receptor like-1 (ORL-1) are heptahelical inhibitory Gi-protein coupled receptors anchored in the lipid raft domains of the cell membrane [64]. The main routes through which opioid tolerance is established are receptor desensitization and internalization. Repeated or continuous activation results in the phosphorylation of opioid receptors leading to G-protein uncoupling, β-arrestin (βArr) binding, receptor endocytosis and through that, the degradation

Effect of membrane lipid environment on purine, NK1, TLR and endocannabinoid functions

Purine P2X receptors have also been found in lipid rafts in primary cultures of cerebellar granule neurons and in brain or DRG extracts [18,20]. P2X3 is a trimeric cation channel gated by extracellular adenosine triphosphate (ATP) and it is expressed by most sensory ganglion neurons. It is involved in pain transmission, CGRP can increase P2X3 receptor activity and, therefore, has a role in processes related to inflammation, migraine and chronic pain [81]. There is a functional P2X3 upregulation

Summary and conclusions

Due to the difficulties and challenges of developing novel analgesics, alternative drug development opportunities are increasingly coming into focus. Most ion channels and receptors involved in pain sensation and processing, such as thermosensitive members of the TRP superfamily, TPV1, TRPA1, TRPM3, TRPM8 and some other TRP channels, ORs, P2X receptors, NK1R, TLR4 and CB1R are proven to be located in the lipid microdomains of the plasma membrane. Based on several in vitro and in vivo findings

CRediT author statement

Andrea Nehr-Majoros: Visualization; Software, Writing – original draft, Ágnes Király: Writing – original draft, Éva Szőke: Conceptualization; Funding acquisition; Resources; Supervision; Writing – original draft; Writing – review & editing, Zsuzsanna Helyes: Funding acquisition; Writing – review & editing.

Funding

This research was funded by research grants No. TKP2021-EGA-13, TKP2021-EGA-16 grants which have been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the EGA 13 and EGA 16 funding scheme co-financed by the EU. The work was supported by PTE-ÁOK-KA-2021-09 and OTKA-138936. This work was also supported by the Hungarian Research Network (HUN-REN), Chronic Pain Research Group and by The National Research, Development and

Declaration of competing interest

None.

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