TRP Channels Role in Pain Associated With Neurodegenerative Diseases

Abstract

Transient receptor potential (TRP) are cation channels expressed in both non-excitable and excitable cells from diverse tissues, including heart, lung, and brain. The TRP channel family includes 28 isoforms activated by physical and chemical stimuli, such as temperature, pH, osmotic pressure, and noxious stimuli. Recently, it has been shown that TRP channels are also directly or indirectly activated by reactive oxygen species. Oxidative stress plays an essential role in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, and TRP channels are involved in the progression of those diseases by mechanisms involving changes in the crosstalk between Ca²⁺ regulation, oxidative stress, and production of inflammatory mediators. TRP channels involved in nociception include members of the TRPV, TRPM, TRPA, and TRPC subfamilies that transduce physical and chemical noxious stimuli. It has also been reported that pain is a complex issue in patients with Alzheimer's and Parkinson's diseases, and adequate management of pain in those conditions is still in discussion. TRPV1 has a role in neuroinflammation, a critical mechanism involved in neurodegeneration. Therefore, some studies have considered TRPV1 as a target for both pain treatment and neurodegenerative disorders. Thus, this review aimed to describe the TRP-dependent mechanism that can mediate pain sensation in neurodegenerative diseases and the therapeutic approach available to palliate pain and neurodegenerative symptoms throughout the regulation of these channels.

Keywords: Alzheimer’s disease; Parkinson’s disease; TRP channels; neurodegeneration; pain.

FIGURE 1

TRP channels expressed in the nervous system cells. Several members of the TRPC, TRPV, TRPM, and TRPA families are highly expressed in cells of the central and peripheral nervous system (neurons, astrocytes, oligodendrocytes, and microglia). TRP families are represented by capital letters as follow, C, TRPC; M, TRPM; V, TRPV; A, TRPA. Numbers indicates specific members of each family.

FIGURE 2

SOCE through TRP channels. Activation of G-protein coupled receptors activates the phospholipase C pathway that induces the hydrolysis of PIP₂ to DAG (red arrows) that actives PKC, which in turn phosphorylates TRP channels. In parallel, the generation of IP₃ (green arrows) promotes the release of Ca²⁺ from the ER. The depletion of intracellular Ca²⁺ stores from the ER is sensed by STIM1, which also activates Ca²⁺ channels in the plasma membrane such as TRPs (dark green arrow), allowing the entry of Ca²⁺ from the extracellular medium to the cytosol (black arrows) to refill de ER deposits.

FIGURE 3

Alterations in calcium homeostasis mediated by SOCE during inflammation and oxidative stress. Activation of G-coupled receptors by pro-inflammatory mediators, such as bradykinin, induces the release of Ca²⁺ from the ER stores through the PLC pathway (green arrows), followed by an influx of Ca²⁺ through Ca²⁺ permeable channels such as TRPs (black arrows). The increase [Ca²⁺]i then induces mitochondrial dysfunction that leads to caspase activation, ROS and RNS production, microglia activation, and production of pro-inflammatory mediators (yellow arrows).

FIGURE 4

TRP channels are expressed in brain structures involved in pain perception. Pain processing includes cortical (prefrontal, parietal, somatosensory, and cingulate), limbic (amygdala, hippocampus, thalamus, hypothalamus), and movement-related structures (Basal Ganglia, Substantia Nigra, and Cerebellum) that express several members of the TRP channels. TRP families are represented by capital letters as follow, C, TRPC; M, TRPM; V, TRPV; A, TRPA. Numbers indicates specific members of each family.