Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

Abstract

Chronic pain is a debilitating condition that affects roughly a third to a half of the world’s population. Despite its substantial effect on society, treatment for chronic pain is modest, at best, notwithstanding its side effects. Hence, novel therapeutics are direly needed. Emerging evidence suggests that calcium plays an integral role in mediating neuronal plasticity that underlies sensitization observed in chronic pain states. The endoplasmic reticulum and the mitochondria are the largest calcium repositories in a cell. Here, we review how stressors, like accumulation of misfolded proteins and oxidative stress, influence endoplasmic reticulum and mitochondria function and contribute to chronic pain. We further examine the shuttling of calcium across the mitochondrial-associated membrane as a mechanism of cross-talk between the endoplasmic reticulum and the mitochondria. In addition, we discuss how endoplasmic reticulum stress, mitochondrial impairment, and calcium dyshomeostasis are implicated in various models of neuropathic pain. We propose a novel framework of endoplasmic reticulum–mitochondria signaling in mediating pain hypersensitivity. These observations require further investigation in order to develop novel therapies for chronic pain.

PACAP-38 Induces Transcriptomic Changes in Rat Trigeminal Ganglion Cells Related to Neuroinflammation and Altered Mitochondrial Function Presumably via PAC1/VPAC2 Receptor-Independent Mechanism

“…It is plausible therefore that the migraine headache-inducing effect of PACAP is generated with the involvement of mitochondria. Regarding the importance of mitochondria in nociceptive sensory neurons, there is accumulating evidence demonstrating mitochondrial dysfunction in several chronic pain conditions and pain is a common complaint in patients with mitochondrial diseases [53][54][55]. Mitochondria together with the endoplasmic reticulum are key regulators of intracellular calcium homeostasis which set neuronal excitability.…”

The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

“…Neuroinflammation involves glial cells (microglia and astrocyte) activation, chemokines (CCL1, CCL2, CCL7, CXCL1) release and pro-inflammatory mediators (TNF-α, IL-1β, IL-18, BDNF, PGE2) secretion in pain neural circuitry that, subsequently, mediates excitatory neuronal plasticity and synaptic transmission for producing and sustaining chronic inflammatory pain, chronic neuropathic pain, chronic fracture-associated pain, as well as chronic cancer pain ( Zhang et al, 2013 ; Ji et al, 2014 ; Ni et al, 2019 ; Qiang and Yu, 2019 ; Wang et al, 2020b ). Accumulating evidence emphasizes that oxidative stress drive neuronal apoptosis and sensitize nociceptors in the pathogenesis of chronic pain, such as chemotherapy-induced peripheral neuropathy (CIPN) and opioid-induced hyperalgesia (OIH) ( Zhang et al, 2014 ; Shu et al, 2015 ; Grace et al, 2016a ; Yousuf et al, 2020 ; Squillace and Salvemini, 2022 ). Nevertheless, the involvement of specific molecular signaling in neuroinflammation and neuronal apoptosis remains controversial.…”

Endoplasmic Reticulum Stress in Chemotherapy-Induced Peripheral Neuropathy: Emerging Role of Phytochemicals

“…The known associated primary molecular mechanisms involve a decline in translation and transcription output [ 42 ], and axonal transport [ 43 ], alteration in ionic homeostasis sodium ion (Na + ), calcium ion (Ca 2+ ), and potassium ion (K + ) [ 44 ], microtubular alterations [ 45 ], ER stress induction [ 46 ], mitochondrial function impairment [ 47 ], and disturbed oxidative homeostasis [ 9 , 48 ]. However, mechanism-based targeting of CIPN requires investigation to develop targeted therapies.…”