Molecular Mechanisms of Chronic Pain and Therapeutic Interventions

Abstract

Chronic pain imposes incalculable health and economic burdens, affecting more than 30% of the global population in published studies. Optimal management of chronic pain is imperative for individuals experiencing such distress. Nevertheless, the current approaches to chronic pain assessment and treatment fail to meet clinical requirements. In recent years, there has been a growing recognition of the need for precision medicine approaches to effectively manage chronic pain. Chronic pain can be classified into three categories: nociceptive (resulting from tissue injury), neuropathic (caused by nerve injury), or nociplastic (arising from a sensitized nervous system). These classifications significantly impact the evaluation and treatment decisions at all levels. Significantly, in practice, there is substantial overlap in chronic pain mechanisms among patients and within different types of chronic pain. The application of precision medicine is imperative in the management of chronic pain. This review offers a comprehensive overview of the distinctive molecular mechanisms underlying nociceptive, neuropathic, and nociplastic pain, including immune responses, ion channels, monoaminergic imbalance, and neuroinflammation. Subsequently, we summarized the status quo of nociceptive, neuropathic, and nociplastic pain manipulation. Last, we explored the advances in pain management strategies for chronic pain that are making significant progress toward their clinical implementation.

Keywords: molecular mechanism; neuropathic pain; nociceptive pain; nociplastic pain; therapeutic interventions.

FIGURE 1

Illustrative drawing showing the various manifestations of nociceptive, neuropathic, and nociplastic pain, along with molecular mechanisms.

FIGURE 2

Ion‐channels involved in sensory‐spinal circuits in the development of neuropathic pain. Upregulation, increased density, and enhanced function of proexcitatory ion channels, such as Navs, TRPs, Cavs, purinergic (P2X and P2Y) channels, ASICs, and HCNs, contribute to the augmentation of neurotransmitter release, neuronal excitability, and ectopic firing in peripheral sensory neurons, DRG, and spinal dorsal cord. This is further enhanced by the downregulation of potassium channels, such as the diminished inhibition of the TRPM8 due to decreased potassium channels in DRG. Cavs indicates voltage‐gated calcium channels; DRG, dorsal root ganglion; HCNs, hyperpolarization‐activated cyclic nucleotide‐gated channels; Navs, voltage‐gated sodium channels; TRPs, transient receptor potential channels; TRPM8, transient receptor potential (TRP) transient receptor potential melastatin 8. The red arrow signifies an increase or decrease, while other‐colored arrows indicate secretion.

FIGURE 3

Interactions between nociceptive neurons and immune cells implicated in the development of neuropathic pain in peripheral nerves, DRG, and CNS. Neutrophils and proinflammatory macrophages are rapidly recruited to sites of nerve injury or damage, as well as DRG, and play a role in the development of NP by proinflammatory mediators, including TNF‐α, IL‐1β, BDNF, NO, and PGE2. Macrophages in the DRG are essential for initiating and maintaining mechanical allodynia induced by nerve injury through interaction between axotomized CSF1⁺ sensory neurons and CSF1 receptor‐positive macrophages. Additionally, there is an increase in macrophage numbers dependent on TLR4‐ and MCP‐1‐mediated mechanisms Similarly, fibroblasts produce proalgesic mediators such as NGF and IL‐6 that drive sensitization of peripheral neurons to promote neuropathic pain. The pain‐inducing effects of effector T cells are ascribed to the proinflammatory T_H1 and T_H17 subtypes, which produce their respective effector cytokines IFNγ and IL‐17. T cell‐derived cytokine IL‐17 directly activates TRPV1 nociceptors, thereby contributing to the induction of mechanical allodynia. The Schwann cells and SGCs play a significant role in pain sensation after nerve injury through the release of various inflammatory mediators. Furthermore, the blood–nerve barrier is disrupted by Schwann cells through the release of MMP‐9. Peripheral nerve injury induces an upregulation of TNF‐α, and BDNF, components signaling in microglia within the CNS. Microglia also degrade the perineuronal nets and prune inhibitory interneuron synapses in the dorsal horn, thereby contributing to NP. Following nerve injury, astrocytes experience a decline in their capacity to regulate the balanced levels of extracellular K+ and glutamate due to increased Cx43, thereby causing an increase in neuronal excitability. Furthermore, nerve injury induces the upregulation of CXCL13 in spinal cord neurons, thereby activating astrocytes through CCR5 signaling pathway to sustain neuropathic pain. The injury to the nerves also triggers an upregulation of SP4 in spinal cord and cortical astrocytes, thereby facilitating neuropathic pain through the generation of new synapses and reorganization of somatosensory cortical circuits. In addition, the activation of S1P receptor found on spinal astrocytes triggers the activation of inflammasomes. Finally, IL‐33 derived from oligodendrocytes may act on spinal microglia, astrocytes or endothelial cells to facilitate synaptic transmission. BDNF indicates brain‐derived neurotrophic factor; CCR5, chemokine (C‐C motif) receptor 5; CNS, central nervous system; CSF1, colony stimulating factor 1; Cx43, connexin‐43; CXCL13, chemokine (C‐X‐C motif) ligand 13; IFNγ, interferon gamma; IL‐6, interleukin 6; IL‐17, interleukin 17; IL‐1β, interleukin‐1 beta; IL‐33, interleukin 33; NGF, nerve growth factor; TNF‐α, tumor necrosis factor alpha; TLR4, toll‐like receptor 4; MCP‐1, monocyte chemoattractant protein 1; MMP‐9, matrix metalloproteinase‐9; NO, nitric oxide; NP, neuropathic pain; PGE2, prostaglandin E2; S1P, sphingosine‐1‐phosphate; SGCs, satellite glial cells; TRPV1, transient receptor potential vanilloid 1; TSP4, thrombospondin‐4. The red arrow signifies an increase or decrease, while other‐colored arrows indicate secretion. The plus sign (+) signifies promotion.

FIGURE 4

Neuroimmune mechanisms relevant to nociplastic pain syndromes in both the peripheral and CNS. Nociplastic pain syndromes involve a variety of complex pathophysiological mechanisms, primary including neuroimmune interactions, central sensitization, monoaminergic unbalance, and peripheral sensitization. The increased neutrophils and SGCs in sensory ganglia is crucial for the promotion of heightened pain sensitivity and sensitization of dorsal horn cells to harmful stimulation in nociplastic pain. The upregulation of pronociceptive molecules, such as TNF‐α, IL‐1β, and HMGB1, released from glial cells enhance neuroinflammation and pain signaling in CNS. For example, microglia TLR4 activation by HMGB1 contributes to microglia stimulation and neuroinflammation leading to the development of chronic nociplastic pain. Activation of TLR4 and TLR7 has been shown to enhance the activity of TRPV1 and TRPA1 channels, respectively, thereby facilitating neuronal excitability through enhancing Ca²⁺ influx, substance P as well as CGRP release. Enhanced excitatory signaling through glutamate and reduced GABA expression in the CNS contributes to central sensitization. Moreover, microglia release proinflammatory cytokines and pronociceptive neurotrophic factors into the CNS, thereby promoting the development of neuroinflammation and central sensitization. The descending pain modulatory system, involving endogenous opioids, noradrenaline, serotonin, dopamine, and endocannabinoid, plays an important role in the development of nociplastic pain. AMPA indicates a‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; BDNF, brain‐derived neurotrophic factor; CGRP, calcitonin gene‐related peptide; CNS, central nervous system; GABA, gamma‐aminobutyric acid; α5‐GABA, α5 subunit containing GABA type A; HMGB1, high‐mobility group box 1 protein; IL‐1β, interleukin‐1 beta; NGF, nerve growth factor; NMDA, N‐methyl‐D‐aspartate receptor; PAG, periaqueductal grey; RVM, rostral ventromedial medulla; TNF‐α, tumor necrosis factor alpha; TLR, Toll‐like receptor; TRPV1, transient receptor potential vanilloid 1. The red arrow signifies an increase or decrease, while other‐colored arrows indicate secretion. The plus sign (+) signifies promotion.