Pain is a protective perception of nociceptive stimuli that indicates that the body is facing potential harm. However, when it persists for 3 months or more, it becomes chronic pain and becomes an important problem affecting human physical and mental health, affecting an estimated 1.5 billion people worldwide. There are not many clinically available treatment options, and opioids such as morphine have many adverse effects (such as sedation and constipation), rapid tolerance, abuse and even the risk of death. Only by recognizing pain can we find a treatment solution. Immunity and Pain Physiology Pain is mediated by classical neurotransmitters and neuropeptides, such as glutamate, calcitonin gene-related protein (CGRP), and substance P. However, considerable evidence suggests that many immune pathways mediated by glial cells (such as astrocytes and microglia), immune cells, cytokines, and chemokines, cause pathological pain. Current pain therapies ignore the role of these non-neuronal contributors. Immune cells secrete cytokines and pattern recognition receptors expressed on immune cells are activated after peripheral nerve injury or infection. Ligand interactions with TLRs and NLRs activate, ultimately activating nuclear NF-κB and AP-1-mediated pro-inflammatory intracellular pathways, as well as inflammasome activation, with increased synthesis of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, CCL2/MCP-1, and CX3CL1, as well as other immune mediators such as nitric oxide (NO). Within 3 days of injury, macrophages and neutrophils are recruited to the site and secrete cytokines (TNF-α, IL-1β, IL-6, IL-17, nerve growth factor (NGF), serotonin, histamine, prostaglandins), help helper T cells and B cells, and increase peripheral pain receptor sensitivity. Activated immune cells also release anti-inflammatory molecules (IL-10, etc.) as an autoregulatory method in the healing process and homeostatic reconstruction. Neurons express cytokine receptorsSensory neurons express a number of cytokine receptors (IL-1βR, TNF αR, IL-6R, and IL-17RA), NGF receptors (TrkA), and G-protein-coupled receptors for serotonin, histamine, and PGE2. Sensitization of peripheral neurons leads to enhanced release of nociceptors from terminal synaptic excitatory neurotransmitters, an important site for sensory signal regulation. This enhanced posterior horn signaling further sensitizes second-order sensory neurons through a mechanism called central sensitization. With the development of central sensitization, nociceptive neurons are able to effectively signal higher-order structures in the brain and brainstem to produce pathological pain sensations, including hyperalgesia (an enhanced response to normal noxious stimuli) and ectopic pain (pain in response to normal, non-noxious stimuli, such as light touch).
Central nervous system immune cells astrocytes are distributed throughout the brain and spinal cord and outnumber neurons, accounting for 40-50% of all central nervous system glial cells. In contrast, microglia make up only 5-10% of all glial cells and are considered to be resident mononuclear phagocytic cells of the central nervous system. As with injury or infection of the central nervous system, damage to peripheral nerves stimulates increased expression of glial activation markers in the dorsal horn of the spinal cord, such as GFAP, and microglia activation markers such as complement receptor 3 (CR3), CD11b, or ionized calcium-binding adapter molecule 1 (Iba1). Astrocytes and microglia express pain-associated neurotransmitter receptors, such as the AMPA (α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) receptor, metabotropic glutamate receptor (mGluR), purinergic receptor (eg, P2X4R or P2X7R), or neurokinin 1 receptor (NK1R), which are released by neurotransmitters (glutamate, ATP and substance P) activation. Following peripheral nerve injury, neurons also release chemokines such as CCL2 and CX3CL1, as well as other immune mediators CSF-1 and ATP. These released factors effectively activate astrocytes and microglia, which in turn release pro-inflammatory cytokines (e.g., IL-1β, TNF-α, and IL-6), chemokines (e.g., CCL2), ATP, excitatory amino acids (EAAs), and NO. Like peripheral cells, dorsal horn neurons express receptors for many of these factors. Activation of cytokine receptors expressed in neurons can alter the function of neurons. For example, the pro-inflammatory cytokines TNF α and IL-1β enhance excitatory synaptic transmission in neurons in layer II of the spinal cord and inhibit inhibitory synaptic transmission. TNF-α enhanced the frequency of spontaneous excitatory postsynaptic currents (sEPSC), while IL-6 decreased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs). It is worth noting that IL-1β is able to increase the frequency and amplitude of sEPSC while decreasing the frequency and amplitude of sIPSC. In addition, TNF-α and IL-1β enhanced excitatory AMPA and nmda-induced currents, while IL-1β and IL-6 inhibited inhibitory GABA- and glycine-induced currents. Thus, the activation of these cytokine receptors further sensitizes local neurons, leading to feed-forward loops of nociceptive signals.
Resources
: Zimney, K.; Van Bogaert, W.; Louw, A. The Biology of Chronic Pain and Its Implications for Pain Neuroscience Education: State of the Art. J. Clin. Med. 2023, 12, 4199. https://doi.org/10.3390/ jcm12134199
Smith PA (2023) Neuropathic pain; what we know and what we should do about it. Front. Pain Res. 4:1220034. doi: 10.3389/fpain.2023.1220034
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