4.4: Physiology of Pain

The concept of pain, originating from the Greek word signifying "penalty," is deeply rooted in the human experience. Pain is a protective mechanism swiftly triggered in response to tissue damage or harm. Its primary function is to elicit a reaction, prompting individuals to remove or mitigate the source of the pain. Remarkably, individuals devoid of pain perception often face a perilously abbreviated lifespan due to the accidental injuries they sustain.

In tandem with other sensory processes, pain perception involves four distinct stages. The initial phase, known as transduction, entails the conversion of painful stimuli into action potentials. Subsequently, the transmission phase ensues, where these action potentials, now laden with pain signals, travel through dedicated axonal pathways to the CNS. Within the CNS, the third stage, perception, unfolds. The ultimate step in this intricate process is the modulation of pain. In this phase, the body deploys intrinsic mechanisms to diminish pain intensity. Pain modulation represents a dynamic and adaptive response to ensure an individual's well-being in the face of discomfort or injury.

Transduction

Pain emerges when tissue damage activates nociceptors. The name nociceptor is derived from the Latin word "Nocere," meaning to hurt. Nociceptors are characterized by their unmyelinated, branched, and versatile nature. They transduce various stimuli into action potentials. Notably, nociceptors exhibit a remarkable diversity among sensory neurons, as a single type of stimulus can elicit responses from multiple receptor types. These receptors are on peripheral nerves and are concentrated within the skin, soft tissues, muscles, joint surfaces, arterial linings, periosteum, and the connective tissue lining the cranial vault (dura mater). However, they are absent from the brain and are relatively sparse on most visceral organs.

Contrary to many other sensory neurons, nociceptors exhibit minimal adaptation, responding slowly or not at all. They are susceptible to stimuli that either threaten tissue damage or actively cause it. When the intensity of a stimulus surpasses a particular threshold, it is categorized as noxious, indicating its potential to inflict tissue harm.

Nociceptors are polymodal in nature as they are activated by three primary types of stimuli: thermal stimuli exceeding 45 degrees Celsius, mechanical stimuli such as pressure or deformation, and chemical stimuli. The latter category encompasses many molecules, including hydrogen ions, potassium ions, bradykinin, histamine, acetylcholine, leukotrienes, ATP, and proteolytic enzymes released due to tissue damage. Bradykinin, histamine, and leukotrienes are associated with inflammation. Both bradykinin and histamine act as vasodilators among other roles they play in the body. Additionally, substances such as prostaglandins, substance P, and serotonin modulate the sensitivity of pain nerve endings, although they do not directly induce excitation. Substance P plays a multifaceted role by stimulating vasodilation and histamine release from mast cells. Histamine-induced vasodilation, in turn, augments local blood flow, initiating the process of inflammation. In the broader context, inflammation serves as a vital protective mechanism against infection or injury, underscoring the indispensable role of pain in safeguarding our overall well-being.

Nociception and the complex mechanisms underlying pain perception involve many intricate players. Acid-sensing ion channels play a pivotal role in mediating acid nociception, contributing to the perception of pain in response to acidic stimuli. Concurrently, vanilloid receptors or transient receptor potential (TRP) channels, distributed across both C and A-δ fibers, play a substantial role in the intricate web of thermal, mechanical, and chemical nociception. Furthermore, the opioid system, inextricably entwined with the nociceptive process, comprises three G-protein-coupled receptors: the μ-, δ-, and κ-receptors. These receptors seamlessly interact with their corresponding endogenous ligands—β-endorphin, enkephalin, and dynorphins. Peripheral opioid receptors are situated within primary sensory neurons, where they remain relatively quiescent until prompted by noxious stimuli. Among the renowned pain-relieving drugs, morphine stands out as a prime example, predominantly exerting its effects through μ-opioid receptors and serving as a potent agent in the management of severe pain conditions.

Nociceptors employ a myriad of intricate signaling pathways. These pathways exhibit a profound connection to ion channels, with some pathways mediated by G-proteins and their downstream agents, including adenylate cyclase, cAMP, cGMP, IP3, and PLC. In contrast, other pathways entail a direct cellular response. These receptors respond to diverse stimuli, including capsaicin, vanilloid compounds, thermal fluctuations, and low pH, with minimal involvement in mechanical transduction. Conversely, an alternative subset of ion channels, referred to as ENaC/degenerin channels, predominantly serve as mechanoreceptors, adept at detecting mechanical stimuli. Adding to the complexity, acid-sensing ion channels come into play, responding sensitively to lactic acid and thereby contributing to pain perception, particularly in conditions like angina.

Transmission

Two distinct types of peripheral neurons carry out pain signal transmission: Aδ and C fibers, each with unique characteristics. Aδ fibers, characterized by myelination, conduct action potentials rapidly, ranging from 6 to 30 m/s. Predominantly located in the skin and muscle, these fibers primarily transmit swift, sharp pain signals. Aδ fibers typically respond to mechanical or thermal pain stimuli and employ excitatory amino acid neurotransmitters, notably glutamate and aspartate, to convey their messages. In contrast, C fibers are unmyelinated and dispersed in muscle, mesentery, abdominal viscera, and periosteum regions. Due to their unmyelinated nature, pain signals are conveyed at a much slower pace, spanning 0.5 to 2 m/s. The pain relayed by C fibers is often described as dull or burning in character. These fibers exhibit responsiveness to a broader range of stimuli, encompassing mechanical, thermal, and chemical injuries.

Figure 4 | Neural Pathways for Pain Transmission | ⁸ This diagram illustrates the transmission of pain signals from the periphery to the cerebral cortex via the spinothalamic tract. Pain signals originate from a source of pain, where two types of primary afferent fibers are involved: A-delta fibers (myelinated, fast-conducting, associated with acute pain) and C fibers (unmyelinated, slow-conducting, associated with chronic pain). These fibers synapse in the dorsal horn of the spinal cord, where their cell bodies are located in the dorsal root ganglion. The pain signals are then transmitted via the spinothalamic tract through the brainstem and thalamus, ultimately reaching the cerebral cortex, where pain perception occurs.

Both Aδ and C fibers originating from the dorsal root ganglion travel through multiple spinal cord segments before reaching the gray matter of the dorsal horn (Figure 4). Here, they synapse with second-order neurons, categorized into two distinct types: nociceptive and wide-dynamic-range (WDR) neurons. Nociceptive neurons exclusively receive input from Aδ and C fibers. In contrast, WDR neurons possess a wider receptive field, responding to information from both nociceptive and non-nociceptive neurons, including Aβ fibers. Glutamate, released by both Aδ and C fibers, initiates a cascade of events by binding to AMPA receptors on the second-order neurons, thereby eliciting action potentials and perpetuating the signal transmission to higher levels of the CNS.

Substance P, primarily released by C fibers, assumes a pivotal role within the spinal cord, where the initial synapse occurs. Here, it augments and prolongs the actions of glutamate. Notably, levels of substance P surge during persistent pain, contributing to the modulation of pain perception.

The journey of second-order neurons progresses as they cross the midline of the spinal cord via the anterior commissure and ascend through the anterolateral pathway of the spinothalamic tract, ultimately reaching the thalamus. This multifaceted relay system ensures the transmission of pain signals to higher centers within the CNS).

Perception

Perception involves relaying pain-related data to the brain, facilitated by two primary routes: the spinothalamic tract via the dorsal root ganglion and from the trigeminal ganglion. These tracts ascend towards various brain regions, encompassing the reticular formation, periaqueductal gray, limbic system, hypothalamus, basal ganglia, as well as the primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices. The thalamus is also a crucial relay point within this intricate pathway. Notably, subcortical regions, including the brain stem, amygdala, and cerebellum, contribute significantly to the multifaceted experience of pain, thus underscoring the complexity of pain perception and processing.⁹

Modulation of Pain

The modulation of nociception can manifest at various stages along the afferent sensory pathway, contributing to the intricate perception of pain. Such modulation may arise at the very source of the pain stimulus or at any juncture within the ascending sensory pathways where synaptic transmission occurs. Additionally, the modulation of nociception can be orchestrated through descending efferent inhibitory pathways that originate at the level of the brainstem (Figure 5).

Peripheral modulation of nociception is primarily achieved through releasing or removing endogenous inflammatory mediators in the proximity of nociceptors. Several mediators, including ATP, glutamate, cytokines, kinins, and trophic factors, are produced at the inflammation site and can potentially sensitize and activate nociceptors.

Local anesthetics, such as lidocaine, function by reversibly binding to channels and obstructing sodium ion conduction, thereby inhibiting nerve transmission. Furthermore, analgesic effects can be achieved through drugs like aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), including both nonspecific cyclooxygenase (COX-1) inhibitors and specific cyclooxygenase (COX-2) inhibitors. These drugs work by impeding the action of the enzyme COX, which plays a crucial role in converting arachidonic acid into prostaglandins. By reducing prostaglandin synthesis, NSAIDs effectively modulate nociception at peripheral sites. Additionally, corticosteroids exert their influence by affecting cyclooxygenase pathways and other related pathways to suppress inflammation.

Figure 5 | Effects of Various Chemical Agents in the Modulation of Pain Transmission |​ ¹⁰ Local anesthetics, such as lidocaine, inhibit nerve transmission, whereas anti-inflammatory drugs offer analgesic effects. Various descending pathways, including opioidergic and adrenergic inputs, modulate pain at the dorsal horn.

The modulation of nociception at the spinal cord level is a multifaceted process governed by the influence of both excitatory and inhibitory neurotransmitters within the dorsal horn. The dorsal horn of the spinal cord acts as the central relay station for pain signals originating from A- δ and C nerve fibers, for the local frequency of pain impulses, and for interpretations transmitted from higher-level centers within the CNS. In this critical hub, pain nerve fibers establish synaptic connections with non-nociceptive nerve fibers, facilitating the integration of pain-related information. Moreover, the brain wields formidable descending pathways that transform pain input.

Figure 6 | Pain Modulation - Descending Pathways |¹¹ This flowchart illustrates the process of pain modulation through descending pathways in the CNS. The periaqueductal gray plays a central role in pain modulation, coordinating descending inhibition and facilitating pain relief by activating endogenous enkephalinergic neurons. These neurons stimulate the release of neurotransmitters such as serotonin, leading to the modulation of pain signals.

Within the brainstem, the descending pain-modulating pathway interfaces with various higher-level brain regions, including cingular-frontal areas, the amygdala, and the hypothalamus. The interaction between the cingular-frontal regions and the descending modulatory system represents a pivotal avenue of pain modulation in humans. The periaqueductal gray, enriched with inputs from diverse brain regions, can exert a profound analgesic effect. Concurrently, the rostral ventromedial medulla inhibits nociceptive information and contributes to the control of descending pain processes.

Descending inhibitory pathways originating from higher cerebral centers, such as serotonergic neurons, project to the dorsal horn of the spinal cord, where they effectively suppress pain transmission. Another prominent inhibitory pathway is the noradrenergic system. The locus coeruleus, located in the pons near the junction of the pons and the midbrain, is the largest group of noradrenergic neurons in the CNS that projects throughout the brain and spinal cord. Elevating the concentration of norepinephrine and serotonin within the synaptic cleft inhibits the propagation of nerve impulses responsible for transmitting pain signals to the brain. The communication of nociceptive information among various neurons relies on chemical signaling mediated by both excitatory and inhibitory amino acids, as well as neuropeptides.

The endogenous opioid system assumes a pivotal role in pain modulation. An opioid descending inhibitory pathway liberates endorphins and enkephalins, which operate presynaptically to hyperpolarize nerve fibers. This action effectively counteracts the pain signal in the form of action potentials as they traverse the ensuing synapse and lead to the release of neurotransmitters. Exogenous opioids like morphine function as agonists at opioid receptors dispersed throughout the CNS (Figure 6). They use mechanisms of action to hinder the release of substance P (presynaptic) or involve postsynaptic inhibition through the inhibitory G-protein pathway, ultimately decreasing cAMP levels. Enkephalin elicits presynaptic inhibition by obstructing calcium ion channels, subsequently impacting the release of substance P.

The thalamus, the relay center, serves as the primary locus for the initial awareness of pain, constituting a rudimentary perception. The comprehensive interpretation of pain occurs upon relay to the cerebral cortex. The pain signal is subject to more precise perception and thorough analysis to determine the requisite action upon reaching the cerebral cortex.

Activities such as exercise, stress, acupuncture, and hypnosis activate the endogenous opioid system, leading to enduring analgesic effects. The anticonvulsant Gabapentin enhances the release of GABA, an inhibitory neurotransmitter, thereby impeding the further transmission of pain signals. Tricyclic antidepressants, known for elevating serotonin and norepinephrine levels, are postulated to contribute to their pain-relieving effects.¹²

Gating Mechanism

Within the complex web of pain transmission, one key modulation site resides in the dorsal horn, serving as the gateway for pain impulses en route to the spinothalamic system. The substantia gelatinosa, also known as the gelatinous substance or Rexed's lamina II, is a specific region within the dorsal horn of the spinal cord (Figure 7). It spans several segments of the spinal cord, primarily in the cervical, thoracic, and lumbar regions, and plays a crucial role in the modulation of pain signals. It contains inhibitory interneurons that play a crucial role in the gating mechanism. Upon activation by various inputs, including both nociceptive and non-nociceptive stimuli, gating cells can exert inhibitory or facilitatory effects on projection neurons. This modulation occurs through complex interactions involving neurotransmitters such as GABA, glycine, and glutamate, as well as neuromodulators like serotonin and endorphins.

Figure 7 | Substantia Gelatinosa | ¹³ This figure provides an overview of the substantia gelatinosa of the dorsal horn of the spinal cord in modulating nociceptive signaling. The substantia gelatinosa serves as a critical site for the integration and modulation of incoming sensory information, particularly pain signals.

Melzack and Wall proposed the gate control theory of pain in 1965. Under normal, pain-free circumstances, an inhibitory interneuron in the substantia gelatinosa maintains a state of inactivity, effectively preventing the onward projection of pain signals to the brain—the gate remains securely closed. However, the dynamic interplay of action potentials in specific nerve fibers can significantly influence the state of this gate.

When an action potential arises within a C fiber, which typically conveys pain signals, it exerts an inhibitory effect on the inhibitory interneuron. This inhibition, in turn, releases the gate from its closed position, allowing pain signals to proceed towards the brain. Conversely, when an action potential is generated in an Aβ fiber—a conduit for sensory information related to touch—a collateral branch activates the inhibitory interneuron, even in the presence of concurrent C fiber activation. This intricate interaction results in the closure of the gate, effectively impeding the transmission of pain signals (Figure 8).¹⁴

Figure 8 | Gate Control Theory of Pain |¹⁵ Gating cells play a pivotal role in regulating the transmission of nociceptive signals to higher brain centers. The diagram illustrates how gating cells can influence this transmission by either enhancing or suppressing synaptic transmission between primary afferent fibers and projection neurons. This process effectively "gates" the flow of nociceptive information, thereby regulating pain perception.

Understanding the role of the substantia gelatinosa and the gate control mechanism has led to the development of pain management strategies that involve non-noxious sensory input, such as transcutaneous electrical nerve stimulation and acupuncture, to alleviate pain. As an illustrative example, gentle rubbing is a prime instance of Aβ fiber activation, stimulating the inhibitory interneuron and ensuring the gate remains tightly closed.

Hyperalgesia

Hyperalgesia is a heightened sensitivity to pain resulting from damage to nociceptors or the sensory neurons responsible for transmitting pain signals. This heightened sensitivity can manifest locally in specific areas or diffusely across the entire body. There are two forms of hyperalgesia. Primary hyperalgesia occurs when damage to a particular tissue increases sensitivity to pain near the injured site. In other words, the tissue directly affected by injury becomes more sensitive to painful stimuli. Secondary hyperalgesia, in contrast, arises when the surrounding tissues, not directly damaged themselves, become more sensitive to painful stimuli. Such heightened sensitivity extends beyond the immediate area of injury and affects the adjacent healthy tissues. These two types of hyperalgesia collectively contribute to an individual's perception of pain. They are significant factors in understanding the complex nature of pain sensation and its modulation in response to injury or damage to the nervous system.¹⁶

Visceral Pain

Visceral pain emanates from the internal organs, where the density of pain receptors is relatively low. Consequently, visceral pain perception tends to be diffuse and characterized by a dull, aching quality, often making it challenging to pinpoint the precise source of discomfort. Visceral pain contrasts with somatic pain, which typically arises from injuries or tissue damage. The pain receptors are more abundant in somatic pain, resulting in a sharper or tingling sensation. This distinction in pain perception is vital in clinical assessments to differentiate between sources of discomfort within the body.¹⁷

Referred Pain

When particularly intense visceral sensations reach the threshold of conscious perception, they can manifest in unexpected locations within the body. For instance, powerful, visceral sensations originating from the heart may be perceived as pain radiating to the left shoulder and left arm. This non-standard pattern of conscious perception of visceral sensations is called "referred pain." The specific areas to which referred pain is projected to depend on the affected organ system (Figure 9). Although the precise mechanism behind referred pain remains incompletely understood, the prevailing theory suggests that visceral and somatosensory fibers from the location of referred pain enter the spinal cord at the same vertebral level and may synapse on the same second-order neuron. According to this explanation, sensory fibers from the mediastinal region, where the heart is situated, would enter the spinal cord at the same level as the spinal nerves from the shoulder and arm. Consequently, the brain misinterprets the sensations from the mediastinal region as originating from the axillary and brachial regions. It is important to note that projections from the cervical ganglia's medial and inferior divisions also enter the spinal cord at these middle to lower cervical levels, further contributing to this phenomenon.¹⁸

Figure 9 | Referred Pain | ¹⁹ This chart shows how conscious perception of visceral sensations is mapped to specific regions of the body. Some sensations are felt locally, whereas others are perceived as affecting areas quite distant from the involved organ.​