The Nociceptive System: The Anatomy of Pain

Nociception is the neural process of encoding noxious stimuli. It differs from pain as a subjective experience, although it often precedes it. This distinction is important: sensory neuron activity is not the same as pain, and pain is possible even with altered signal processing without overt tissue damage. [1]

The nociceptive system is an end-to-end circuit from free nerve endings in the skin and organs through the spinal ganglia and brainstem to the thalamus and cortex. It consists of the first neuron with its cell body in the spinal or trigeminal ganglion, the second neuron in the posterior horns of the spinal cord or the nuclei of the trigeminal complex, and the third neuron in the thalamus with a projection to the cortex. This multi-level arrangement allows for the simultaneous encoding of the intensity, localization, and affective significance of stimuli. [2]

Clinically, knowledge of the anatomy of the tracts determines the interpretation of symptoms and focal sensory losses. Damage to the lateral spinothalamic tract produces characteristic contralateral pain and temperature sensitivity disturbances below the level of the lesion, whereas peripheral damage alters both pain and other modalities in the corresponding nerve zone. [3]

Modern terminology emphasizes the following types of pain: nociceptive, neuropathic, and nociplastic. The latter describes pain arising from altered nociception without evidence of ongoing tissue damage or overt disease of the somatosensory system. This requires consideration of not only peripheral receptors but also central networks, their plasticity, and modulation. [4]

Peripheral apparatus of nociception

Peripheral nociceptors are typically free nerve endings of primary afferents. Based on axon type, a distinction is made between thinly myelinated A-delta and unmyelinated C-fibers. A-delta fibers mediate rapid conduction and "primary" pain, while C-fibers mediate slow, aching pain and post-traumatic hyperalgesia. [5]

Molecularly distinct subpopulations of nociceptors exist. Peptidergic C-afferents express calcitonin gene-related peptide and substance P, whereas non-peptidergic ones frequently bind isolectin B4 and express P2X3 receptors. These groups differ in part in their tissue targets and in their input to spinal lamina, resulting in distinct pain physiologies. [6]

Nociceptors are widely distributed: skin, periosteum, joint capsules, muscle fascia, endoneurium, vascular walls, and visceral structures. Axon diameter and conduction velocity vary, which influences the temporal profile of "fast" and "slow" pain. A-delta fibers typically exhibit velocities of up to tens of meters per second, while C-fibers exhibit a fraction of this. [7]

The cell bodies of primary nociceptors are located in the spinal dorsal root ganglia and in the trigeminal ganglion for the orofacial region. Their central processes enter the posterior roots of the spinal cord or the caudal spinal nucleus of the trigeminal nerve, providing the first synaptic processing level. [8]

Table 1. Types of peripheral nociceptors and fibers

Class	Axons	Speed of execution	Preferential incentives	Main mediators
A-delta mechanothermal	Thinly myelinated	Up to tens of meters per second	Strong mechanical and thermal	Glutamate
With peptidergic	Unmyelinated	Units m per sec	Polymodal nociceptive	Substance P, CGRP
Non-peptidergic	Unmyelinated	Units m per sec	Chemical, mechanical	ATP via P2X3

Transduction: Nociceptor Sensors and Mediators

Channels of the TRP family play a key role. TRPV1 is activated by heat, acid, and capsaicin; TRPA1 by electrophilic stimuli and cold in some species; and TRPM8 by cold and menthol. These channels mediate cation entry and trigger the action potential, and their sensitization underlies hyperalgesia. [9]

Purinergic P2X3 receptors and P2X2-P2X3 heteromers on nonpeptidergic neurons respond to ATP release from damaged cells. P2X3 inhibitors demonstrate analgesic potential in preclinical and early clinical studies, particularly in visceral and neuropathic pain conditions.[10]

In tissue acidosis, acid-sensing ion channels of the ASIC family are activated, particularly ASIC3, which is important for pain in muscles, joints, and visceral organs. A decrease in pH causes depolarization of nociceptors and increases their excitability. [11]

Inflammatory mediators enhance transduction. Nerve growth factor, via the TrkA receptor, increases the expression and sensitivity of ion channels, while bradykinin, via B2 receptors, rapidly increases the excitability of human sensory neurons and further sensitizes TRPV1. These mechanisms explain hyperalgesia in the area of inflammation. [12]

Table 2. Receptors and channels of primary nociceptors

Target	Main incentives	Cellular localization	Clinical significance
TRPV1	Heat, acid, capsaicin	Peripheral endings of C and A-delta	Desensitization-based analgesics
TRPA1	Electrophiles, irritants	C-fibers	Role in neuropathic pain
P2X3	ATP	Non-peptidergic C	Candidate antagonists for chronic pain
ASIC3	Acidosis	C and A-delta	Musculoskeletal and visceral pain
TrkA	NGF	Peptidergic C	Anti-NGF antibody therapy

First central entrance: ganglia, Lissauer tract and posterior horn

The central processes of primary afferents from the dorsal root ganglia and trigeminal ganglia enter the dorsal horn, where the first synapse is formed. Some fibers branch and distribute their input across several segments, which expands the field of reflex responses and signal integration. [13]

Before entering the gray matter, many thin afferents enter the dorsolateral bundle of Lissauer, where they give off short ascending and descending collaterals to 1-2 segments, after which they enter the lamina of the dorsal horn. This is an important anatomical substrate for intersegmental integration of nociceptive information. [14]

The dorsal horn is characterized by a laminar architecture according to Rexed. The most significant for pain are the superficial laminas I and II, where C and a significant portion of the A-delta afferents terminate, as well as laminae V with wide-dynamic-range neurons integrating cutaneous and visceral inputs. [15]

Glutamate predominates at primary afferent synapses, and the neuropeptides substance P and CGRP bind to them. These act on second-order receptors, including NK1, enhancing transmission and promoting central sensitization. The contribution of individual peptides is context-dependent, as confirmed by new genetic models. [16]

Table 3. Laminae of the dorsal horn and main inputs

Lamina	Main afferents	Characteristic neurons	Role
I	A-delta, C	Projections into the spinothalamic and spinoparabrachial tracts	Nociceptive specific responses
II (gelatinose substance)	C, part A-delta	Inhibitory and excitatory interneurons	"Entrance gate" and modulation
V	Skin and visceral, wide range	Wide dynamic range	Convergence and referred pain

Interneuronal networks and inhibition

Local interneurons set the pain transmission threshold. The main inhibitory neurotransmitters—GABA and glycine—limit the excitability of projection neurons and inhibit the spread of excitation between laminae. Disruption of these systems leads to increased pain responses. [17]

The canonical "gate" concept has received direct support: a glycinergic nutrient brake operates in the dorsal horn, separating the light touch and pain pathways. Loss of this brake after peripheral nerve injury contributes to mechanical allodynia. [18]

Chronic pain involves forms of disinhibition and circuit rewiring, including changes in the recruitment and properties of inhibitory interneurons. This leads to lower thresholds, expanded receptive fields, and the emergence of pathological responses to non-threatening stimuli. [19]

Glial cells also exhibit laminar specialization and are involved in network plasticity. Astrocytes and microglia, through cytokines, purines, and growth factors, alter neuronal excitability and network resilience to overload, which is important for the chronicity of pain processes. [20]

Table 4. Interneurons of the dorsal horn and their functions

Type	Mediator	Main connections	Function
GABAergic	GABA	Lamina II to I and V	Increasing the pain threshold
Glycinergic	Glycine	Nutrient brake on projection neurons	Prevention of allodynia
Exciting	Glutamate	Intralaminar and interlaminar	Input gain and distribution

Ascendant pain pathways

The spinothalamic tract is the main pathway to neocortical areas. Projection neurons from lamina I and NK1-positive cells from laminar layers III-IV transmit signals to the ventral posterior and intralaminar nuclei of the thalamus, providing sensory discrimination and arousal.[21]

The spinoreticular tract projects to the reticular formation of the medulla oblongata and pons, then to the medial thalamic nuclei. It is associated with motivational-affective aspects of pain, attention, and sleep disturbances associated with chronic pain syndromes. [22]

The spinoparabrachial tract ascends to the parabrachial nucleus of the pons, then to the amygdala, insula, and hypothalamus. This pathway is particularly important for the affective and defensive components and is actively involved in the formation of chronic pain in neuropathy. [23]

Orofacial signals follow the trigeminal pathways: primary afferents in the trigeminal ganglion, synapses in the spinal trigeminal nucleus, then to the ventral posteromedial nucleus of the thalamus and the cortex. There are ventral and dorsal trigeminothalamic tracts with different lateralization. [24]

Table 5. Main ascendant paths and their goals

Path	Source	Intermediate stations	Thalamic nuclei	Bark
Spinothalamic	Laminae I, III-IV	Lateral funiculus	Ventral posterior, intralaminar	Primary and secondary somatosensory
Spinoreticular	Deep layers of the posterior horn	Reticular formation	Medial	Cingulate gyrus, association areas
Spinoparabrachial	Lamina I	Parabrachial nucleus	Through the paralimbic nodes	Islet, tonsil
Trinigothalamic	Spinal trigeminal nucleus	Pons, midbrain	Ventral posteromedial	Facial cortex in the somatosensory area

Thalamus and cortical representations

The thalamus is the main distribution hub for nociceptive signals. The ventral posterior nuclei encode localization and intensity, while the medial and intralaminar nuclei encode motivational-affective aspects and the state of wakefulness. This multinuclear distribution explains the complexity of the pain experience. [25]

Cortical representations include primary and secondary somatosensory areas for discrimination, the insula for interoception and "sensation bodies," and the anterior cingulate cortex, associated with motivational-affective components and behavioral regulation. Coordinated ensembles of these areas form a subjective map of pain. [26]

Affective flow from the parabrachial nucleus to the amygdala enhances learned avoidance responses, anxiety, and the formation of persistent patterns of hyperarousal. Increased conductivity in this circuit is considered one of the mechanisms of chronicity. [27]

Conceptually important, plasticity of the dorsal horn networks and thalamocortical circuits maintains and enhances pain during prolonged nociceptive stimulation. This justifies a multi-level approach to therapy – from peripheral targets to integration centers. [28]

Table 6. Thalamocortical projections of nociceptive signals

Nucleus of the thalamus	Main entrance	Main projections	Function
Ventral posterior	Spinothalamic, trinigothalamic	Primary and secondary somatosensory	Localization and intensity
Intralaminar	Spinothalamic, spinoreticular	Diffuse association zones	Wakefulness, attention
Medial	Paralimbic pathways	Cingulate gyrus, insula	Affective significance

Visceral nociception and referred pain

Visceral afferents converge widely with cutaneous and deep somatic inputs on lamina I and V neurons. This creates the phenomenon of referred pain, where visceral pathology is perceived as superficial or muscular in specific dermatomes and sclerotomes.[29]

Spinal processing of visceral information is characterized by wide divergence and intersegmental distribution, making precise source localization difficult. This explains the diffuse nature of visceral pain, frequent autonomic co-reactions, and variability in irradiation. [30]

In the orofacial region, the ventral posteromedial nucleus of the thalamus and its connections with the insular cortex are of particular importance. Neuroimaging and experimental data indicate a key role for these projections in the propagation and modulation of trigeminal pain. [31]

Individual subtypes of defense, such as itch, utilize overlapping but partially distinct pathways, including the spinoparabrachial pathway, to transmit to structures that generate the motivation to scratch. This underscores the modularity of the organization. [32]

Table 7. Features of visceral and orofacial nociception

System	Convergence	Thalamic targets	Clinical consequences
Visceral	High with somatic on laminae I and V	Medial and intralaminar nuclei	Referred pain, blurred localization
Orofacial	Segmental in the trigeminal complex	Ventral posteromedial	Neuropathic facial pain, migraines

Practical markers: from fibers to therapeutic targets

Conduction physiology helps interpret clinical symptoms. Rapid "first" pain corresponds to the A-delta input, while slow, aching pain corresponds to the C-component. Conduction threshold and velocity change with inflammation and neuropathy, which is reflected in sensitivity tests and reaction times. [33]

Damage to the lateral cord with loss of spinothalamic fibers results in contralateral loss of pain and temperature sensitivity, while a lesion in the trigeminal complex nuclei produces specific orofacial phenotypes. This allows for the topical localization of lesions in neurological disorders. [34]

Molecular targets have been validated by genetics and pharmacology. The NaV1.7 channel, encoded by SCN9A, is critical for nociception, but selective inhibitors have not yet met expectations in clinical trials. Anti-NGF strategies, as well as P2X3 antagonists and TRPV1 modifiers, are promising, considering the balance of efficacy and tolerability. [35]

Understanding of the parabrachial-tonsillar circuit and lateral anterolateral pathways is evolving based on high-precision anatomical and functional studies. This opens the way to circuit-directed interventions and combined approaches that address the sensory and affective components of pain. [36]

Table 8. Key molecular targets and status of evidence

Target	Justification	Clinical status
NaV1.7 (SCN9A)	Genetic syndromes of painlessness and pain	Selective inhibitors with variable results
NGF-TrkA	Nociceptor sensitization and hyperalgesia	Anti-NGF antibodies in studies and registrations according to indications
P2X3	Visceral and neuropathic pain	Antagonists in clinical trials
TRPV1	Polymodal transduction and desensitization	Topical and invasive approaches, safety optimization continues

Brief summary

The nociceptive system is a multilayered network, extending from peripheral sensors to thalamocortical assemblies. Its anatomy explains the phenomena of "first" and "second" pain, referred pain, allodynia, and chronicity. Progress in the molecular identification of nociceptor subtypes, spinal networks, and ascending pathways forms the basis for personalized therapies targeting not only peripheral receptors but also affective-motivational circuits. [37]