Introduction

The nervous system is an incredibly intricate portion of human anatomy that serves four major functions: motion, sensation, association, and control of homeostasis.1 It is broadly characterized into the central nervous system (CNS) and the peripheral nervous system (PNS); both of which play roles in pain pathways.

Pain systems are neural circuits responsible for the sensation and perception of pain, as well as the body’s response to pain. They consist of peripheral neurons (primary afferent neurons) with sets of peripheral receptive elements (nociceptors) that connect in the dorsal horn of the spinal cord with central neuronal relay pathways (secondary afferent neurons) and integrative neurons that modulate nociceptive signals through excitatory or inhibitory influences at various levels of the neuraxis.2 Nociception encompasses four stages: transduction, transmission, modulation, and perception. During transduction, a physical or chemical stimulus is converted into an electrical signal that can then be transmitted. Transmission refers to the movement of this electrical activity through the nervous system. Modulation is the alteration of neuronal activity through the pathways of transmission. Lastly, perception is when somatosensory transmission results in the subjective experience of pain.3

When there is traumatic injury and/or persistent inflammatory changes, this can affect the normal pain pathways, which can result in chronic pain. The progression from acute pain to a chronic pain state involves multilevel changes, including the primary sensory neuron, spinal cord, and brain.4 At the initial site of injury inflammatory mediators are secreted that stimulate nociceptor activity, this is sometimes referred to as the “Inflammatory soup”. The “inflammatory soup” is made up of peptides, neurotransmitters, lipid, and neuropeptides that can either activate nociceptors or lower their threshold to activation leading to increased activation of the a-delta and c fibers and peripheral sensitization occurs.5

Evolution of Neuromodulation to the Current Devices and Waveforms

The application of electrical stimulation for treating chronic pain has been observed since the first century C.E. when it was observed that contact with electrical fish could relieve gout pain.6 The modern application of neuromodulation for chronic pain began in the 1950s with deep brain stimulation and gained further momentum in the 1960s with the publication of Melzack and Wall’s gate control theory.6,7

Neuromodulation is a broad term that describes the modification of neurological function through delivery of a stimulus to specific targets.8,9 The modalities can be electrical, magnetic, chemical, and/or genetic. In chronic pain management, neuromodulation involves the use of non-invasive, minimally invasive, and/or surgical electrical therapies to modulate or alter the perception of pain.6 Commonly applied techniques of neuromodulation in the treatment of chronic pain involve spinal cord stimulation, peripheral nerve stimulation, and deep brain stimulation.10

Current neuromodulation devices can be broadly classified as open-loop stimulation or closed-loop stimulation. Open-loop systems provide a train of impulses to anatomic targets continuously or on a fixed cycle and can be activated/deactivated and adjusted by either the patient or an operator but do not adjust automatically.8,11 Closed-loop systems adjust their stimulation automatically, in real time, according to some form of clinically relevant physiologic data, such as postural changes affecting the distance of the epidural electrodes to the spinal cord detected through evoked compound action potentials.8,11

Traditional spinal cord stimulation, which was the standard treatment for the first four decades of therapy, is open-loop, low-frequency, and a tonic form of stimulation that is delivered at frequencies ranging from tens to hundreds of hertz, at an intensity that induces a paresthesia yet does not elicit a motor response or cause discomfort.11 Paresthesia coverage historically was thought to be of the utmost importance in predicting patient pain relief as documented by Barolat; however, current research suggests that with certain programs and frequency settings, paresthesia coverage is not required.12 Burst stimulation was initially introduced for chronic neuropathic pain treatment in 2010. It involves delivering a series of high-frequency pulses periodically at a lower rate.11,12 A meta-analysis comparing burst stimulation to tonic stimulation for the management of chronic low back pain demonstrated superiority of burst stimulation over tonic stimulation.13 This meta-analysis design represents the highest level of peer-reviewed evidence and suggests reproducibility.

Sub-perception stimulation, also referred to as paresthesia-free stimulation, is stimulation that does not reach the threshold of perception (paresthesia), due to low amplitude, waveform design, ultra-low frequency or high-frequency.11 High-density or high-dose stimulation is a type of stimulation that is meant to provide a higher charge per second (dose) at a relatively high frequency; typically, with an amplitude that has been adjusted below that which would elicit a paresthesia.11,12 High-frequency therapy, 10-kHz, utilizes a higher frequency with a shorter pulse-width to obtain pain relief without eliciting any paresthesia. This form of therapy is paresthesia independent and thus lead placement is based solely on anatomical landmarks,12 although some patients do complain of uncomfortable stimulation at very high amplitudes.

Basic Mechanisms of Pain Types of Neurons

Neurons are found all throughout the human body and serve a multitude of different sensory and motor functions. Neurons consist of similar structures: soma (cell body), axon, and dendrites. The three major types of neurons are sensory, interneurons, and motor. Sensory neurons involved in detecting physical and chemical noxious stimuli are called nociceptors. They consist of cell bodies that arise in the dorsal root ganglion and axonal processes that travel to the periphery or centrally into the spinal cord. Nociceptors can be activated by temperature, mechanical, and chemical stimuli.

Types of Axons

Axons consist of various nerve fibers that conduct action potentials from the terminal dendrites to the axonal terminals or from one neuron to another.2 Nociceptors are primarily characterized by their axonal-free endings, fiber diameter or conduction velocity.14 The two primary afferent neurons are Aδ fibers and C fibers. Type Aδ fibers are medium diameter myelinated afferents that convey acute, well-localized, sharp pain. They are the smallest myelinated fibers, with a diameter of 2–5 µm and a conduction velocity of 30 m/s. C fibers are unmyelinated and transmit poorly localized stimuli, with a slower conduction velocity of 2 m/s. Type Aδ fibers are primarily thermal and mechanical nociceptors, whereas type C fibers are polymodal and respond to thermal, mechanical, and chemical stimuli.

Action Potentials in Neurons

An action potential is a sequence of changes in the voltage across a membrane of a cell that is created by a depolarizing current. When Na+ ions enter the cell, they result in increase in the voltage in the cell, taking it from its resting potential to its threshold potential. Once the threshold potential has been reached, complete depolarization occurs. Once peak potential has been reached, the Na+ channels return to their resting state and K+ channels are activated, resulting in hyperpolarization.15 The speed of transmission of the action potential is directly correlated to the diameter of the axons and the presence of myelin.16 Nodes of Ranvier, or gaps in the myelin sheath, allow in an increase in the conduction velocity. Action potentials ultimately allow for release of terminal neurotransmitters.

Synaptic Transmission in the Synaptic Cleft

Chemical synapses are mediated through the secretion of neurotransmitters at the level of the synaptic cleft.17 Synaptic signals are received by the terminal dendrites and soma and are transmitted within the neuron via axons. Depolarization results in an influx of calcium ions into the axon terminal, which bind to the calcium-sensing proteins that directly interact with soluble-ethylmaleimide-sensitive-factor activating protein receptor (SNARE) proteins. These are responsible for the fusion of the synaptic vesicles, which contain neurotransmitters, to the presynaptic axon terminal membrane, resulting in release of the neurotransmitters into the synaptic cleft. The neurotransmitters then diffuse across the synaptic cleft and bind to specific ion channels that are located on the postsynaptic neuron’s membrane.

Routes of Pain Transmission

Transmission is one of the three fundamental steps in the perception of pain. Transmission refers to the relay of the nociceptive signals from the periphery to the spinal cord. This begins when the primary afferent nociceptors release neurotransmitters in the dorsal horn, which activate second-order neurons. The second-order neurons cross contralaterally at the level of the spinal cord and ascend as the spinothalamic tract to project into the brain stem and thalamus.18 Third-order neurons are located at the level of the thalamus and project impulses to the primary sensory cortex for further processing and pain perception.

Types of Pain Nociceptive Pain

Nociceptive input injury activates peripheral Transient Receptor Potential (TRP) nociceptors, leading to depolarization and action potential propagation to the dorsal root ganglia.16 Here, pseudounipolar neurons (first-order) receive this input and send axonal processes to the spinal cord’s dorsal horns.19 These axons synapse in the spinal gray matter, affecting second-order neurons, which cross the spinal cord and ascend in the anterolateral aspects of the spinal cord (becoming one of the tracts comprising the anterolateral pathways) towards the medulla oblongata, pontine and midbrain tegmentum. Eventually, these neurons synapse the thalamus’s ventral posterior nucleus (VPL). From the VPL, the information traveling in the spinothalamic tract is conveyed via thalamic somatosensory radiations (the third-order neurons of this pathway) to the primary somatosensory cortex in the postcentral gyrus (Brodmann areas 3, 1, 2).20 However, it is important to highlight that pain and temperature sensation for the face as carried by an analogous pathway, the trigeminothalamic tract. The Anterolateral Pathways are composed mainly by three tracts: spinothalamic (previously described), spinoreticular tracts, and spinomesencephalic tract. The spinothalamic and spinoreticular tracts together convey emotional and arousal aspects of pain; the spinoreticular tract terminates in the medullary–pontine reticular formation, projecting to intralaminar thalamic nuclei project diffusely to the entire cerebral cortex and is involved in the behavioral arousal caused by the nociceptive stimulus and spinomesencephalic (participates in central modulation of pain).21

Modulatory Output

Pain modulation represents a complex process, encompassing interactions among local neural circuits in the spinal cord’s dorsal horn and extensive modulatory inputs from farther regions (Figure 1). The Gate Control Theory posits that sensory signals from wide-diameter, non-painful A-β fibers are key in diminishing pain transmission at the dorsal horn of the spinal cord.22 This concept is utilized in therapeutic approaches like transcutaneous electrical nerve stimulation (TENS), where A-β fibers are stimulated to mitigate chronic pain.17

Figure 1 Route of pain transmission.

The periaqueductal gray stands out as a pivotal component in pain modulation, receiving signals from the hypothalamus, amygdala, and cortex. It significantly contributes to the inhibition of pain transmission at the dorsal horn, mainly through a pathway at the pontomedullary junction, particularly within the rostral ventral medulla (RVM).23 The RVM is notable for its serotonergic (5-HT) neurons, originating from the raphe nuclei, which extend to the spinal cord and play a role in pain modulation.23 Furthermore, it transmits inputs via substance P to the locus ceruleus, thereby affecting noradrenergic pathways that regulate pain in the spinal cord’s dorsal horn. Histamine also plays a role in this complex modulation mechanism, particularly through its action on H3 receptors. Opiate medications like morphine are key players in pain modulation. Enkephalin and dynorphin are primarily concentrated in the periaqueductal gray, RVM, and spinal cord dorsal horn, while β-endorphin-containing neurons are predominantly located in regions of the hypothalamus that project to the periaqueductal gray.23,24 This intricate network of pathways and modulators underlines the complexity of pain perception and its regulation in the human body.

Neuropathic Pain

Neuropathic pain is defined as pain resulting from direct damage to the somatosensory nervous system.25 The symptoms of neuropathic pain can be classified as either positive or negative sensory symptoms. Positive symptoms, arising from nociceptive hypersensitivity, include allodynia, hyperalgesia, and paresthesia.26 Conversely, negative symptoms, which result from afferent neuronal injury, lead to incomplete input to the nervous system and are characterized by hypoalgesia and hypoesthesia. Diagnosing neuropathic pain involves a comprehensive history and physical examination, and confirmation can be achieved through histological, electrophysiological, and structural imaging tests.27

Treatment of neuropathic pain typically begins with pharmacotherapy, which includes tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and calcium channel ligands.28–31 If initial therapy fails, interventional methods can be a viable treatment approach.9,32 These procedures include steroid injections/neural blockade, neuroablative procedures, transcranial/epidural stimulation, spinal cord stimulation, deep brain stimulation, and percutaneous stimulation.33 Additionally, emerging methods being explored include gene therapy, strategies targeting ion channels, and the use of optogenetics and chemogenetics.34

Inflammatory Pain

Inflammatory pain is characterized by heightened sensitivity due to the inflammatory response associated with tissue damage.35 This response is triggered by extracellular inflammatory mediators released from the surrounding damaged tissues and nociceptive fibers.

These mediators encompass a variety of substances that are released upon cell damage, as well as those that are generated following tissue injury. Proinflammatory substances include reactive oxygen species, protons, kinins, prostanoids, bradykinin, adenosine triphosphate, serotonin, histamine, cytokines, neurotrophins, and neuropeptides.26

Mechanisms of Hyperalgesia and Allodynia

Hyperalgesia and allodynia are positive sensory neuropathic symptoms resulting from nociceptor hypersensitivity.23 The IASP Task Force defines hyperalgesia as increased pain sensitivity,36 while allodynia is characterized as pain due to a non-nociceptive stimulus.36 The mechanisms underlying hyperalgesia and allodynia include the upregulation of nociceptive pathways and a failure to inhibit these pathways.

Multiple mechanisms have been identified concerning the upregulation of the nociceptive pathway, with the two primary ones being peripheral and central sensitization.37 Peripheral sensitization occurs due to alterations in the unmyelinated C and myelinated A-delta fibers, leading to hypersensitivity. These changes at the molecular and cellular levels cause neurons to become abnormally sensitive to noxious stimuli.38 Central sensitization involves modifications within the spinal cord.27 Electrical stimulation of sensory nerves at C fiber intensity leads to the spinal release of amino acids, including glutamate and neuropeptides, such as substance P, and neurotrophic factors, such as brain-derived neurotrophic factor, culminating in spinal upregulation.

The failure of the nociceptive system’s inhibitory mechanism, leading to hyperalgesia, is referred to as attenuation. Attenuation’s role in inhibition involves both pre and postsynaptic inhibition of nociceptive spinal dorsal horn neurons.36 Conversely, the failure of the inhibitory mechanism in the nociceptive system that results in allodynia is termed separation. The inhibition role of separation entails the suppression of excitatory interneurons, which are responsible for establishing somatotopic borders.36

Peripheral Sensitization

Initially characterized in the 1970’s by Perl et al, peripheral sensitization is defined as increased responsiveness with reduced thresholds of nociceptive neurons to peripheral stimulation.39–41 This phenomenon typically occurs after peripheral nerve injury, tissue injury, and inflammation.41 Deemed primary hyperalgesia, it is believed that injury results in lowered thresholds of primary afferents in response to noxious stimuli, nerve fiber enhanced response to stimuli, and ultimately increase innervation of the injured site by adjacent nerve fibers.42 Post-translational changes to various ion channels have been found to occur at the site of injury resulting in alterations of nerve fiber depolarization with associated changes in gene expression and protein expression.41,43 These changes and associated alterations have been suggested to lead to peripheral sensitization.

Several ion channels have been suggested to be affected by peripheral sensitization, including voltage-gated transient receptor potential vanilloid (TRPV) channels, voltage gated sodium channels, and voltage gated calcium channels. TRPV1 has been seen to be an important channel for pain sensitization and several chronic pain states.44–46 TRPV1 activation allows for increases in intracellular sodium and calcium, triggering membrane action potentials mediating secondary messengers, which subsequently upregulates TRPV1 expression and sensitivity resulting in mechanical and thermal hypersensitivity.41,45,47 Many animal studies have shown that TRPV1 channel knockout mice do not develop the typical thermal and mechanical hyperalgesia after peripheral neurologic insult compared to TRPV1 channel preserved mice. TRPV1 has also been suggested as being necessary to maintain the hyperalgesia state.48,49 In humans, reports of malfunctional TRPV1 resulted in elevated pain thresholds during pain phenotyping experiments.50

Voltage gated sodium channels are expressed in numerous cell membranes for action potential regulation. Several channels including NaV1.1, NaV1.6, NaV1.7, NaV1.8, and NaV1.9 are expressed in a variety of sensory neurons.41 NaV1.7 is of particular interest as it is highly expressed in the dorsal root ganglion, peripheral sensory nerves, and sympathetic neurons.51,52 In animal studies, the loss of function of NaV1.7 resulted in mice with reduced hypersensitivity to pain meanwhile increased NaV1.7 function may be associated with the development of peripheral neuropathic states such as chemotherapy induced peripheral neuropathy and erythromelalgia.18,53,54

Intracellular calcium is an important cellular response leading to neurotransmitter release causing membrane depolarization and act as secondary messengers.55 Two types of calcium channels exist, high voltage (L, N, P, Q, and R type) and low voltage (T type), both of which have been implicated in the pain processing pathways.56 Animal studies with blockade of high voltage calcium channels have shown to decrease subjective pain and hyperalgesia.57–59 Similarly, low voltage calcium channels are important for regulation of nerve fiber excitability. Increased excitability of these channels may help promote the peripherally sensitized state and certain calcium channels are currently investigated as viable drug targets for treatment of chronic pain.60–62 It is theorized that alterations in ion channel regulation ultimately results in protein and neurotransmitter modulation causing the peripherally sensitized state.

Central Sensitization

Central sensitization is characterized as the enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury.63

The concept was hypothesized to explain neuroplastic changes of synaptic function within the central nervous system after the discovery that nociceptive peripheral nerve injuries could sensitize peripheral nociceptive terminals.39,40,64–66 Central sensitization is implicated in multiple rheumatologic and chronic pain conditions including fibromyalgia, arthritis (osteo and rheumatoid), Ehlers-Danlos syndrome, upper extremity tendinopathies, headache, and spine pain.39,67–69 Unique from windup, central sensitization results in lower nociceptive input to create and/or sustain neural activation or potentially allow for amplified responses to non-stimulated or non-nociceptor fibers after cessation of conditioning stimuli.39,70

Several theories have been suggested to explain the pathophysiology of central sensitization though the exact mechanism is unknown. Descending (neural inhibitory) and ascending (neural activating) pathways are often discussed when assessing neuroplastic changes resulting in augmented sensory and pain processing.71

Glutamate is an important neurotransmitter implicated in the development of central sensitization. Glutamate binds to amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-Aspartate (NMDA), and several metabotropic glutamate receptor subtypes (mGluR) in the post-synaptic neurons of the dorsal horn.63,72,73 Activation of the NMDA receptor is essential for initiating and maintaining central sensitization as NMDA receptor antagonism reverses and prevents nociceptive neuronal hyperexcitability.74,75 NDMA activation allows for increased intracellular calcium, inducing intracellular kinases that maintain central sensitization by increasing phosphorylation of the AMPA and NDMA receptors. This results in post-translational modification changing the activity level and trafficking of these receptors and other channels that result in central sensitization.63 Aside from glutamate, substance P and brain derived neurotrophic factor have also been implicated contributing to central sensitization by enhancing C fiber evoked responses.63,76

The anterior cingulate cortex (ACC), periaqueductal grey, subnucleus reticularis dorsalis (SRD), and the rostral ventromedial medulla (RVM) play a large part in the descending pathway.71,77 The RVM and the nuclear raphe magnus contains serotonergic and GABAergic neurons, while dorsolateral posterior tegmentum (DLPT) contains noradrenergic neurons that inhibit neurotransmission at the dorsal horn. Patients with central sensitization have been found to have disrupted descending pathway processing resulting in alterations in serotonin and noradrenergic secretion.78 Patients with fibromyalgia have lower levels of noradrenergic and serotonergic neurotransmitters in bodily fluids as well as fewer opioid receptors but with excess of excitatory neurotransmitters in the pain modulating centers of the brain compared to healthy individuals.79 Functional MRI studies of patients with fibromyalgia and central sensitization have shown significant gray matter reduction in the ACC and prefrontal cortex with otherwise global preservation of gray matter with greater gray matter reduction in patients with long-standing fibromyalgia.68,80 These collective changes in the ascending and descending pain processing pathways have been suggested to contribute to the development of central sensitization.

Neurogenic-Induced Inflammation

Neurogenic-induced inflammation is activation of inflammatory pathways in the Peripheral Nervous System (PNS) and Central Nervous System (CNS) which lead to classical inflammatory reactions and is implicated in chronic pain syndromes. Chronic activation of this inflammatory pathway can lead to peripheral and central sensitization.81 Nociceptors, specified cells which are located in the periphery and, when activated, convey pain to the CNS, can be activated through inflammatory cytokines and neuropeptides such as substance P, calcitonin gene-related protein (CGRP), and neuropeptide Y. Therefore, neurogenic inflammation can directly lead to pain. There is a delicate balance in regards to neuroinflammation since it is appropriately activated in response to deleterious insults on the body (infection, traumatic brain injury, and autoimmune diseases)82 however, this inflammation can persist and lead to chronic pain.83 Chronic neuroinflammation is also seen in chronic inflammatory diseases such as asthma, migraine headaches, psoriasis, and complex regional pain syndrome (CRPS).81 There is a distinction between central and peripheral sensitization, and neurogenic inflammation can be activated in the PNS independently of the CNS due to the blood-brain barrier.

Activation of neurogenic-induced inflammation leads to several major physiologic effects. These include vasodilation of surrounding tissue, leukocyte infiltration, glial cell activation, and increased production of inflammatory mediators.81 Peripheral and central glial cells (Schwann cells, satellite glial cells, microglia, astrocytes, and oligodendrocytes) are the main cell types activated in this process. Signs and symptoms associated with neurogenic inflammation in the periphery can mimic those associated with classical inflammation: erythema, edema, warmth, and pain.

The inflammatory reactions present in the CNS and PNS are different from inflammation in other portions of the body.83 This is due to multiple factors, but a central driver for this is the unique cell types present in the CNS as opposed to other tissues. There is less permeability across the blood-brain barrier, which makes activating the complement cascade more difficult. The implication of this is that T Cells are only involved in extreme conditions and the resident innate immune cells are primarily responsible for interaction with pathogens.83 Neurogenic inflammation can also be triggered solely by increased neuronal activity (including psychological stress) and not necessarily pathogenic insults. Vascular changes associated with early CRPS have been linked to neurogenic inflammation83 as well as psychiatric disorders, such as bipolar disorder, major depressive disorder, anxiety, and cognitive deficits.82

Many of the drugs currently used for pain act to decrease neurogenic inflammation. Interestingly, opioids increase neurogenic inflammation by activating innate immune cells in the CNS.83 These inflammatory changes can also sensitize Lamina I cells to respond to non-noxious stimuli leading to allodynia.84 Vasic and Schmidt have studied hippocampal neurogenesis and have demonstrated that the inflammatory cytokines that are preferentially released in response to neurogenic inflammation can predict a patient’s proclivity to develop chronic pain and can, in contrast, predict resilience to pain.82,84 These inflammatory processes can also initiate structural and functional changes that can lead to ectopic activation of nociceptive pathways.85

Major Types of Segmental and Supraspinal Neurotransmitters

Pain is an unpleasant but vital protective function with biological and psychosocial contributory mechanisms.9,86 The amount of pain experienced is not simply a byproduct of receptor activation and signal transmissions. Instead, it is the summation of signal transmission coupled with segmental and supraspinal modulation. Within this section, we will discuss common segmental and supraspinal neurotransmitters and their role in the facilitation and modulation of pain signal transmission.

Substance P and calcitonin gene-related peptide (CGRP) are neuropeptides found within the DRG and dorsal horn involved in sensitization. Substance P is a Tachykinin87 released within the spinal cord following noxious stimuli. It acts on Neurokinin 1 and 2 receptors which facilitate sensitization by increasing the synaptic actions of excitatory amino acids.88 CGRP has two major forms, alpha and beta, and is expressed by small unmyelinated primary afferent fibers, within the DRG, and superficial layers of the spinal cord.89,90 Together, levels of substance P and CGRP are increased by neuropeptide Y, leading to excitatory effects on wide dynamic range neurons.89

Byproducts of the inflammatory cascade also play an important role in pain facilitation. Bradykinin is a peptide of the kinin family91 that facilitates pain and hyperalgesia through the activation of B1 and B2 receptors.92 This results in activation of phospholipase C, protein kinase C, modulation of transient receptor potential vanilloid 1 (TRPV1), as well as production of prostaglandins and nitric oxide.93 Eicosanoids such as Prostaglandins have been shown to cause a reduced activation threshold of tetrodotoxin-resistant sodium currents in nociceptors and raise intracellular cAMP levels facilitating excitability of sensory neurons.88Leukotriene B4 has been linked to hyperalgesia and found in high concentrations within the joints of Rheumatoid Arthritis patients94 and in concentrations three times higher within the brains of disease groups when compared to controls.95 Cytokines, such as IL-1B and TNF-alpha, can also directly excite and sensitize nociceptive afferent fibers.88 Neurotrophins such as Nerve Growth Factor (NGF) play a role in neurogenic inflammation via both direct and indirect mechanisms.88 Indirectly, NGF is generated by, and also stimulates, mast cell degranulation leading to increased histamine and serotonin release which leads to sensitization of primary afferent fibers.88,96

Tissue damage and the resulting energy mismatch also lead to the accumulation of substances in the extracellular and intracellular milieu which can facilitate pain transmission. Accumulation of the purine nucleotide ATP can itself directly activate nociceptors.97 Additionally, through action at the P2X family of receptors, present within central terminals of primary afferent fibers and lamina V and II of the dorsal horn, ATP can indirectly lead to sensitization by facilitating the release of glutamate.98 Energy crisis also leads to the accumulation of hydrogen ions (H+) which open DRG neuron-specific acid-sensing ion channels DRAISIC/ASIC-3 facilitating sensitization.99,100

Neurotransmitters facilitate pain conduction within the central nervous system through the anterolateral and dorsal column-medial lemniscal pathways with supraspinal input from the brainstem, diencephalic, and cortical structures.88 Glutamate, along with aspartate, are the primary excitatory neurotransmitters that act on excitatory amino acid (EAA) receptors. EAA receptors are found on dorsal root ganglion cells and presynaptic terminals of primary afferent fibers.101 The inhibitory neurotransmitter GABA acts on GABA A receptors located on both unmyelinated primary afferents and DRG cells which may decrease hypersensitivity in neuropathic pain.88

Two additional molecules with both segmental and supraspinal effects are opioids and cannabinoids. Opioids act on µ receptors on peripheral terminals of afferent fibers, within the DRG, and in the central nervous system at the spinal cord, brainstem, and periaqueductal gray (PAG) resulting in both inhibition of ascending nociceptive transmission as well as activation of descending inhibition supraspinally.102 Cannabinoids act on CB1 receptors, which are present centrally and highly expressed within the DRG. Within the DRG cannabinoids decrease the release of neurotransmitters attenuating mechanical and heat hypersensitivity.102,103

Pain Receptors and Their Stimulation

Pain can be categorized into two main types: acute pain and chronic pain. Acute pain typically arises due to direct tissue damage and is often sharp and immediate.104

Acute pain can be broken down into two distinct phases. In the initial phase, the brain sends signals to alert the body to a potential threat or injury, lasting several seconds. The subsequent phase, known as the subacute phase, involves the body’s efforts to initiate protective mechanisms for tissue recovery, spanning hours or longer. The key factor distinguishing pain from nociception is the consciousness of the tissue-damaging stimulus.105 Nociception, involves specialized nerve fibers (nociceptors) that detect potential thermal, mechanical, or chemical stimuli.2 Sensory event perception denotes the transformation of these stimulus events into chemical tissue events, triggering the activation of afferent pathways.106 These afferent pathways generate sensations like pain (nociception), temperature (thermosensation), and touch (mechanoreception). Nociceptors serve as specialized primary afferent neurons responsible for transmitting noxious stimuli to the brain’s higher centers. These receptors have free nerve endings found on cell bodies in the dorsal root ganglia, with axons forming initial synapses with spinal cord cells and extending into the peripheral nervous system.107

Nociceptors are categorized into two primary classes. The first comprises medium-threshold myelinated Aδ-fibers, which convey “first” or rapid pain signals with a diameter of 1–6 μm and a velocity of 5–36 m/s.108 Aδ-fibers function as both mechanical and thermal nociceptors. The second class consists of high-threshold unmyelinated C-fibers, responsible for “second” or slow pain transmission with a diameter of 0.2–1 μm and a velocity of 0.2–1 m/s. These C-fibers specifically serve nociceptive functions.109 Further subcategorization of Aδ-fibers reveals two main classes. Type I (HTM: high-threshold mechanical nociceptors) convey first pain responses to both chemical and mechanical stimuli but possess high heat thresholds (>50). Type II Aδ-nociceptors exhibit much lower sensitivity to thermal stimulation but have notably high mechanical thresholds.106

Various forms of pain arise from different sources: 1. Physiologic pain arises from surface irritation caused by noxious stimuli on skin receptors. 2. Inflammatory pain emerges as a response to tissue injury or subsequent tissue reactions. 3. Neuropathic pain results from a primary dysfunction within the peripheral or central nervous system. 4. Dysfunctional pain stems from malfunctions within the somatosensory system itself, lacking identifiable noxious stimuli.110

The development of these stimuli arises from the response of these nerve fibers, triggering the activation of ion channels/receptors or the release of neurotransmitters.111 Inflammatory mediators are released following injury and inflammation. Consequently, these mediators interact with specific receptors in primary nociceptive neurons.112

The heightened activity in nociceptors leads to the opening of ion channels and receptors, prompting the release of neurotransmitters from central terminals within the spinal cord. This process results in central sensitization (secondary hyperalgesia and allodynia).113 Abnormal expression of receptors and ion channels during chronic pathophysiological states contributes to atypical pain signaling, resulting in persistent pain. Understanding the molecular mechanisms behind these events targets the modulation or altered functions of nociceptors due to inflammation or injury.114

Pain Transmission in the Central Nervous System

Diverse types of information are conveyed to the brain by afferent sensory nerves that consist of receptors. These receptors respond to stimuli within the skin and tissues and are activated by specific stimuli, generating electrical impulses or action potentials within the sensory nerve. Action potentials are transmitted to the nerve cell body located in the dorsal root ganglion within the spinal cord and by way of spinal cord nerves, and are subsequently transmitted through pathways that include the spinothalamic tract. A network in the brain then facilitates the transmission of these signals. From periphery, the sensory information travels along specific pathways.115 It progresses through the pain pathway’s progression and involves different types of nerve fibers with distinctive characteristics. Sensory neurons synapse in the dorsal horn of the spinal cord across specific areas known as laminae with second-order neurons and encompass nociceptive-specific (NS), wide dynamic range (WDR), and low threshold (LR) types. LR neurons only respond to innocuous stimuli whereas NS neurons react to high-threshold noxious stimuli and WDR neurons respond to sensory stimuli.116

These second-order neurons then relay their signal to the thalamus by way of the spinothalamic and spinoreticular tracts. Somatosensory data is processed by the thalamus and neurons are projected to diverse brain regions, such as the insula, anterior cingulate cortex, and the prefrontal cortex, as well as the primary and secondary somatosensory cortices. Thereupon, the intensity, location and duration are integrated leading to the perception of pain.117

Modulation of pain transmission at various points takes place across this pathway. Excitatory and inhibitory interneurons modify pain signals within the spinal cord. Sensory nerves are influenced by receptors like TrkA, TrkB, TrkC, or c-Ret receptors in the dorsal root ganglion and subsequently numerous receptors and neurotransmitters along the pain pathway modulate the pain signal.16,118

There are four major processes in the perception of a painful stimulus.

Initially, primary afferent neurons are activated by a noxious stimulus leading to transduction in peripheral axons. Secondly, in the transmission process, pain impulses travel through a two-fiber system that involves the transmission of slower sensations through C fibers and the fast, sharp sensations by A-delta fibers. Both fiber types terminate in the dorsal horn of the spinal cord. The plasticity of these dorsal horn cells allows for modulation or “gating” of pain impulses.

Second-order neurons continue the transmission to the central nervous system through both the lateral and medial spinothalamic tracts. The duration, location, and intensity of pain, projecting to the ventral posterolateral nucleus of the thalamus is conveyed by the lateral spinothalamic tract to the brain. Conversely, autonomic and unpleasant emotional perceptions of pain are conveyed to the medial thalamus by the medial spinothalamic tract.119 Signal modulation then occurs at the peripheral level altering neural activity along the pain pathway. This modulation can result in the suppression of pain. The fourth process responsible for mediating the localization, and perception of pain involves the projection from the thalamus to specific cortical regions by way of third-order neurons.2,120

Pain Pathways in the Spinal Cord and Brain Stem Neospinothalamic Tract and Paleospinothalamic Tract

The ascending pathways that mediate pain consist of different tracts: the neospinothalamic tract and the paleospinothalamic tract. The “fast” conducting neospinothalamic pathway is involved in conveying the “sharp” pain elicited at the time tissue is damaged. The “slower” conducting paleospinothalamic pathway is involved in conveying the “dull” pain that accompanies the later inflammatory reaction in the damaged tissue as well as temperature and crude touch information.121,122 The first-order neurons are located in the dorsal root ganglion (DRG) for both of these pathways. All first-order sensory fibers, including nociceptive fibers, enter the spinal cord’s dorsal (posterior) grey horn, which is composed of several laminae (Figure 2). Each pain tract originates in different spinal cord regions and ascends to terminate in different areas in the central nervous system. This leads to different pain interpretations the body perceives in the form of acuity, character, and localization.123

Figure 2 Rexed laminae.

There are primarily two types of fibers that transmit pain: A-delta and C-fibers. A-delta fibers are myelinated and have a larger diameter than C-fibers and thus, conduct nerve impulses faster.122 C-fibers are unmyelinated, have a smaller diameter, therefore, have a slower conduction velocity. C-fibers respond to more than one kind of stimulus (thermal, mechanical, or chemical) and thus, are “polymodal” in nature. In contrast, A-delta fibers only respond to one kind of stimulus.122

The neospinothalamic tract, also known as the direct tract, conducts fast and acute pain signals via myelinated A delta fibers. The first-order neuron, again with cell body at the dorsal root ganglion, synapses at the marginal zone, also known as the Rexed Layer I neuron, with the second-order neuron (Figure 3).121 At usually, the same level of the spinal cord, the second-order neuron crosses in the anterior white commissure to the contralateral anterolateral quadrant. This tract is referred to as the lateral spinothalamic tract. The second-order neuron synapses in the thalamus, the ventroposterolateral (VPL) and the ventroposteroinferior (VPI) nuclei. The VPL is thought to be the principal sensory relay nucleus, mainly concerned with site-specific discriminatory functions in the body.122 Neurons in the ventroposteromedial (VPM) nucleus receive nociceptive information from the face. The VPL and VPM are significant for the localization of pain. Thus, the localization of pain occurs at the level of the thalamus and not the cerebral cortex, which is responsible for assessing the quality (type) of the pain, not its location.

Figure 3 Presynaptic and postsynaptic neurotransmitters and their receptors.

The third-order neospinothalamic neuron then synapses on the somatosensory cortex, where it is somatotopically oriented.123 Again, this pathway is responsible for the immediate awareness of a painful sensation and for awareness of the exact location of the painful stimulus.

The paleospinothalamic tract conduct a slow pain signal via unmyelinated C fibers, which is poorly localized in nature. The first-order neuron, as in the neospinothalamic tract, has its cell body at the dorsal root ganglion. This first-order neuron synapses at the substantia gelatinosa and the nucleus proprius, also known as the Rexed Layer II and III neurons, respectively. The nerve cells that furnish the paleospinothalamic tract are multi-receptive or wide dynamic range nociceptors.124

The second-order neurons make quick synaptic connections in laminae IV–VIII of the dorsal horn of the spinal cord. The second-order neurons also receive input from mechanoreceptors and thermoreceptors. Most, but not all, of their axons cross and ascend in the spinal cord primarily in the anterior region and thus called the anterior spinal thalamic tract (AST). Some of the fibers that do not cross ascend in the ipsilateral spinoreticular tract.123,124

These fibers are contained in several tracts, and these fiber tracts are collectively known as the paleospinothalamic tract. Each of them makes a synaptic connection in different locations:123,124

Most (approximately 85%) of these second order neurons synapse in the reticular formation. The reticular formation controls the arousal and wakefulness of the central nervous system. It alerts the cerebral cortex of the perception of pain. From the reticular formation, the third order neuron also sends tracts to the intralaminar nuclei (discussed below). Some (approximately 15%) of these second order neurons synapse in non-specific nuclei of the thalamus which are called intralaminar nuclei. There are two particular nuclei thought to be involved in this tract.123,124Parafasiculus (PR) and Centromedian (CM) Nuclei. From this, third order neurons travel to several different structures including the cingulate gyrus, anterior insular cortex and somatosensory cortex. These structures are thought to be involved in processing the emotional components of pain. The limbic structures, in turn, project to the hypothalamus and initiate visceral responses to pain. The intralaminar nuclei also projects to the frontal cortex, which in turn projects to the limbic structures where the emotional response to pain is mediated. Within this system, there are collateral pathways that form different tracts (spinotectal, spinomesencephalic, spinohypothalamic tracts). These tracts involve important structures including and in the periaqueductal gray (PAG), tectum, amygdala, hypothalamus. Again, these tracts facilitate different aspects of pain including pain suppression, autonomic responses, and emotional association.125Pain Suppression System in the Brain and Spinal Cord Brain’s Opiate System - Endorphins and Enkephalins

Pain is a complex ubiquitous and a fundamental sensory experience that alerts the body to potential threats and promotes self-preservation.126 When pain becomes chronic or overwhelming, it can lead to a myriad of physical and psychological issues and to mitigate the impact of pain, the human body employs a highly evolved pain suppression system that operates in the brain and spinal cord.127 The opiate system consists of a network of receptors, endogenous opioids peptides, including endorphins and enkephalins, playing a key role in pain modulation.103,128

There are three primary types of opioid receptors in the human body: mu (μ), delta (δ), and kappa (κ) receptors. These receptors are distributed throughout the central nervous system, including the brain and spinal cord, as well as the peripheral nervous system.129–131 Each type of receptor has distinct functions in pain regulation and physiological processes. The action of mu, delta, and kappa receptors can be summarized in Table 1.

Table 1 Receptors and Their Action

Neuropeptides in the nervous system play crucial roles in modulating neuronal activity (Tables 2 and 3). Inhibitory neuropeptides, such as somatostatin and enkephalins, dampen neural firing by hyperpolarizing neurons or reducing the release of excitatory neurotransmitters. These neuropeptides help regulate pain perception, anxiety, and overall neural excitability. On the other hand, excitatory neuropeptides, like substance P and dynorphins, stimulate neural activity by depolarizing neurons and increasing neurotransmitter release.89,132 They are involved in processes such as pain transmission, stress responses, and mood regulation. The balance between inhibitory and excitatory neuropeptides is essential for maintaining proper neural function and emotional well-being within the nervous system. The complexity of the neural pathways can be seen in Figure 3.132

Table 2 Excitatory Neurotransmitters and Their Receptors

Table 3 Inhibitory Neurotransmitters and Their Receptors

Endorphins and enkephalins are two families of endogenous opioid peptides that bind to opioid receptors in the brain and spinal cord.128 These peptides are produced within the body and act as natural painkillers. Endorphins are produced in response to stress and pain, and they induce a sense of euphoria and well-being. Beta-endorphins are one of the most well-known endorphins, and they bind primarily to mu receptors, contributing to pain relief. Enkephalins are another group of endogenous opioids that play a significant role in pain modulation. They bind to both delta and mu receptors, providing analgesic effects.

When pain signals are transmitted from peripheral nerves to the spinal cord and brain, endorphins and enkephalins can inhibit the release of neurotransmitters like substance P.133 This inhibition reduces the transmission of pain signals, effectively dampening the perception of pain.

Endorphins and enkephalins can alter the perception of pain by increasing the pain threshold. This means that a person may tolerate a painful stimulus better when the opiate system is activated, resulting in reduced pain perception. Activation of the opiate system can also influence emotional responses to pain. Euphoria and a sense of well-being produced by endorphins can help individuals cope with pain more effectively, both physically and psychologically.

Opioid medications, such as morphine and codeine, work by mimicking the actions of endogenous opioids, and they are used to manage moderate-to-severe pain. The opiate system, with its endogenous opioid peptides like endorphins and enkephalins, plays a pivotal role in regulating pain perception within the brain and spinal cord. Understanding the mechanisms by which these endogenous opioids modulate pain provides valuable insights into both physiological processes and potential therapeutic interventions for pain management.

Pain Processes

Pain is an intricate sensorial experience that involves biological, cognitive and psychosocial factors134,135 Four essential steps encompass the transformation of a noxious stimulus into the awareness of pain: transduction, transmission, modulation and perception at higher cortical centers.136

Transduction

Transduction of pain is a complex process that relates to the conversion of an evoked electrochemical action potential from a mechanical, thermal or chemical noxious stimulus that activates primary afferent first-order neurons distributed throughout the body (skin, viscera, muscles, joints, etc). Inflammatory mediators such as bradykinin, serotonin, prostaglandins, leukotrienes, and cytokines are released from damage tissues, which thereby stimulate these specialized peripheral nociceptors, such as Aδ-fibers and C-fibers. High-threshold receptors respond to mechanical deformation, while polymodal nociceptors respond to a variety of inflammatory chemicals.108,137–139 Their properties are summarized in Table 4.

Table 4 Characteristics of Primary Afferent Fibers

Transmission

Transmission is the process of conveying the nociceptive message from the peripheral nervous system (PNS) to the central nervous system (CNS) by the primary afferent nociceptive neurons (Aδ-fibers and C-fibers). These fibers terminate at the CNS, more specifically at the lamina I and V and I–II of the spinal cord, respectively. Their cell body is located at the dorsal root ganglion (DRG), which sends one branch to the spinal cord and one back to the periphery.3,108,136–139

Peripheral Nervous System

The PNS can be divided into somatic nervous system and visceral nervous system. Each division has a motor and sensory component, including the autonomic nervous system (sympathetic, parasympathetic, enteric). The somatic nervous system includes the sensory system, which consists of cranial nerves (except the optic nerve) and spinal nerves (cervical and lumbosacral plexu