Pain pathways

Types of pain

Pain is divided in several different categories, based on the body region that is involved, the system causing the noxious stimuli, as well as the duration of each painful occurrence (acute versus chronic pain). Furthermore, pain may also be classified based on the exhibited symptoms, the underlying mechanisms and associated syndromes, resulting in three main types:

• Somatic: pain from receptors located in the body surface,
• Visceral: pain from receptors in internal organs,
• Referred: pain perceived in a location different from where the active nociceptors are. 

Pain receptors (nociceptors)

Nociceptors are receptors responsible for the reception of painful stimuli and localize on the skin, joints, viscera, and muscles. These are high-threshold receptors, activated by high-intensity stimuli. Depending on the type of information they relay, nociceptors are divided into four main categories:

• Chemical receptors: activated by both exogenous and endogenous chemical stimuli.
• Mechanical receptors: activated by intense mechanical stimulation (high pressure).
• Thermal receptors: activated by extreme temperatures.
• Polymodal receptors: activated by a variety of high intensity stimuli (chemical, mechanical, thermal).

Silent receptors are another, less prominent type of pain receptors. They are typically found in the joints and remain dormant to chemical, mechanical, and thermal stimuli. They become responsive following the release of inflammatory factors due to tissue damage in conditions such as arthritis.

Pain reception: nociceptors and transduction fibers

Noxious stimuli are detected by specialized primary (or first order) sensory neurons with their cell bodies located in the dorsal root ganglia. These neurons are bipolar (or pseudobipolar), with axon projections to both the periphery and the spinal cord, where they synapse in the dorsal horn. The peripheral terminals of these neurons are free nerve endings, expressing a wide variety of receptors, such as G-protein coupled receptors (GPCRs), and ion channels, such as TRP channels, gated by specific noxious stimuli.

Upon activation, nociceptors generate depolarizing currents that can collectively initiate trains of action potentials. These action potentials reach the dorsal horn of the spinal cord via different types of transduction fibers (axons), carrying sensory information. Based on their diameter and myelination, afferent sensory fibers associated with pain can be classified as follows:

Primary nociceptive afferents can also be classified as peptidergic and non-peptidergic. Peptidergic nociceptors, primarily associated with C fibers (although a few Αδ fibers have also been described), release neuropeptides such as substance P and calcitonin gene related peptide (CGRP), which bind to G-protein coupled receptors in the dorsal horn, modulating pain transmission. Non-peptidergic neurons may have either Aδ or C fibers.

Ascending pathways

The nociceptive fibers terminate in the dorsal horn of the spinal cord. The dorsal horn is divided into ten layers (Laminae of Rexed) based on the cytoarchitectural pattern of the gray matter. Each layer presents specific functional characteristics; Lamina I (marginal zone), for example, is responsible primarily for the transduction of the nociceptive information, while Lamina II (substantia gelatinosa) mediates information processing. This functional specialization is also reflected in the cell types within each layer; Lamina I contains projection neurons and few interneurons, and Lamina II is rich in both excitatory (glutaminergic) and inhibitory (GABAergic, glycinergic) interneurons.

The primary afferents synapse in the dorsal horn in specific patterns. Aδ fibers terminate primarily in Lamina I, with some branching into deeper layers such as V and X. Peptidergic Aδ and C afferents terminate in superficial layers, i.e. Lamina I and the outer region of Lamina II. On the other hand, non-peptidergic C fibers synapse in the central region of Lamina II. Both Aδ and C fibers also reach Lamina V, carrying innocuous stimuli information.

The projection neurons of the dorsal horn, receiving nociceptive input from primary neurons, are termed secondary (or second order) sensory neurons. Their axons cross the midline, ascend the anterolateral quadrant of the spinal cord and terminate mainly in the thalamus (spinothalamic tract). The spinothalamic tract is divided into:

• The lateral division (neospinothalamic tract): Composed of axons from secondary neurons with small receptive fields that project to the ventroposterolateral (VPL) nucleus of the thalamus; this allows for precise localization and discrimination of noxious stimuli.
• The medial division (paleospinothalamic tract): Composed of neurons with large and complex receptive fields that terminate in the intralaminar nuclei of the thalamus. This division is primarily responsible for more generalized responses related to the emotional and cognitive aspects of pain.

Higher cognitive regions

When the secondary neurons reach the thalamic nuclei, they synapse with tertiary (or third order) sensory neurons. Tertiary neurons carry the sensory information to specialized regions, allowing for the nociceptive, emotional, and cognitive aspects of pain. There is no evidence highlighting a specific region that is solely responsible for processing nociceptive information. Secondary sensory neurons of the lateral division of the spinothalamic tract synapse with tertiary neurons projecting to the primary somatosensory cortex (S1). On the other hand, neurons of the medial division, synapse with intralaminar thalamic neurons projecting to the association and prefrontal cortices (PFC). Other regions associated with pain perception include the mid- and anterior cingulate cortex (MCC and ACC, respectively), the insular cortex (AI; anterior insula, PI; posterior insula), the secondary somatosensory cortex (S2), the amygdala, the ventral tegmental area (VTA) and the nucleus accumbens (NAc).

However, these areas do not act independently, but are interconnected, thus forming vast networks responsible for the processing and perception of specific aspects of pain. For example, the prefrontal cortex, with all of the pain-related neocortical regions it encompasses (Brodmann areas 8–14, 24, 25, 32 and 44–47), connects with structures of the limbic system, such as the amygdala. Prefrontal cortex projections have been found to mediate feedforward inhibition to the amygdala; loss of this circuit’s function is known to contribute to the hypersensitivity observed in chronic pain.

Descending pathways

The descending pathways that modulate pain originate from the periaqueductal gray matter (PAG). The PAG receives input from a variety of regions, including the prefrontal cortex, the limbic forebrain, the hypothalamus and the central nucleus of the amygdala. The regulatory role of the PAG is indirect, as it functions through reciprocal connections with the rostroventromedial medulla (RVM).

The RVM is the final key node in the descending pathway, receiving projections from both the PAG and the noradrenergic locus coeruleus. The RVM neurons project to the laminae of the dorsal horn, where they target primary afferent terminals and the cell bodies of secondary neurons that respond to noxious stimuli. The RVM modulates pain bidirectionally, either attenuating (by inhibition) or amplifying the pain signal.

The inhibitory effect of the descending pathways is mediated by endogenous opioid peptides, which act as analgesic neurotransmitters. RVM neurons can activate inhibitory interneurons of the dorsal horn, which then release opioid peptides, such as enkephalin and dynorphin. These peptides bind to μ- and κ-opiate receptors, respectively, of afferent terminals, decreasing neuronal excitability, and thus blocking the transmission of nociceptive signals to higher levels of the central nervous system.

An imbalance in the inhibitory and the facilitatory effect of the PAG-RVM pathway is often the cause of neuropathic and/or inflammatory pain.