Physiology, Nociceptive Pathways

Cellular Level

The receptors responsible for relaying nociceptive information are termed nociceptors; they can be found on the skin, joints, viscera, and muscles. A wide variety of chemical substances activate these receptors, including globulin and protein kinases, arachidonic acid, histamine, nerve growth factor, substance P, calcitonin gene-related peptide (CGRP), potassium, serotonin, acetylcholine, low-pH solutions, adenosine triphosphate (ATP), and lactic acid. Receptors are also activated by temperature extremes, high pressures, and tissue damage causing inflammation.[5][6][7]

Nociceptors can be further subdivided based on the type of information they are relaying. For instance, skin nociceptors can be divided into high-threshold mechanoreceptors (intense mechanical stimulation), thermal receptors (thermal and mechanical stimulation), chemical receptors, and polymodal receptors (high-intensity mechanical, thermal, and chemical stimulation). Joint nociceptors are classified as high-threshold mechanoreceptors, polymodal receptors, and silent receptors. Silent receptors are dormant in normal joints and are unresponsive to stimuli such as heat or pressure. They become responsive only after tissue damage causes the release of inflammatory molecules in conditions such as arthritis. It is believed that patients with arthritis often complain of joint pain at rest due to these receptors suddenly becoming active and causing spontaneous neuronal firing. Additionally, these silent nociceptors may become mechanosensitive following inflammatory induction and can contribute to pain with movement in patients with arthritis. Joint nociceptors are classified as high-threshold mechanoreceptors, polymodal receptors, and silent receptors. Silent receptors are unresponsive to the initial stimuli of heat or pressure, but they become responsive only after tissue damage causes the release of inflammatory molecules. Visceral receptors are classified as mechanoreceptors, thermal, chemical, and silent receptors.[8][9]

Pain perception begins with free nerve endings, which are branches of the primary neuron that are unsheathed at the nerve tips but otherwise surrounded by Schwann cells. The multitude of different receptors conveys information that converges onto neuronal cell bodies in the dorsal root ganglion (stimulus from the body) and the trigeminal ganglia (stimulus from the face). There are 2 major nociceptive nerve fibers: A-delta fibers and C-fibers. A-delta fibers are lightly myelinated and have small receptive fields, which allow them to alert the body to the presence of pain. Due to the higher degree of myelination compared to C-fibers, these fibers are responsible for the initial perception of pain. Conversely, C-fibers are unmyelinated and have large receptive fields, which allow them to relay pain intensity.[10][11][12]

Mechanism

Nociceptive stimuli activate transient receptor potential (TRP) channels on nerve endings, which cause first-order neurons to depolarize and fire action potentials. Action potential frequency determines stimulus intensity. A-delta fibers release glutamate onto second-order neurons, while C-fibers release neuropeptide neurotransmitters. First-order neurons are found in the dorsal root ganglion (stimulus from the body) and trigeminal ganglia (stimulus from the face). A-delta and C-fibers are associated with first-order neurons found in the nucleus posterior marginalis of Rexed layer I and substantia gelatinosa of Rexed layer II. From Rexed layer I and II, these neurons form projections that comprise the 3 major ascending pain pathways: the neospinothalamic, paleospinothalamic, and archispinothalamic tracts.

The neospinothalamic tract begins with nociceptive neurons located in Rexed layer I. Second-order neurons decussate at the anterior white commissure and ascend via the lateral spinothalamic tract. Third-order neurons are in the ventral posterolateral nucleus (VPL) and the ventral posterior inferior nucleus (VPI). From the thalamus, nociceptive information projects to the primary somatosensory cortex for further processing and pain perception. Nociceptive information from the face and intraoral structures is transmitted via first-order neurons in the trigeminal ganglia, which project to the pons and spinal trigeminal nucleus in the medulla before synapsing with neurons in the ventral posteromedial nucleus (VPM), parafascicular nucleus (PF), and the centromedian nucleus (CM). Similar to nociceptive information from the body, the information further projects to the primary somatosensory cortex.

The paleospinothalamic tract is the second of the 3 ascending pain pathways. First-order neurons of this pathway are found in Rexed layer II, which project diffusely to Rexed layers IV through VIII. From the spinal cord, these projections travel anteriorly and project bilaterally onto the mesencephalic reticular formation, periaqueductal gray, tectum, PF, and CM. The PF and CM neurons send projections to the somatosensory cortex, brainstem nuclei, and limbic areas (cingulate gyrus, insulate cortex). The interplay mediates emotional and visceral responses to pain between the limbic structures, hypothalamus, and brainstem nuclei.

The archispinothalamic tract also mediates visceral and emotional reactions to pain. First-order neurons are found in Rexed layer II, which project to neurons in Rexed layers IV and VII. Diffuse projections from the latter 2 layers are sent to the midbrain reticular formation and the periaqueductal gray. Neurons in the midbrain reticular formation and periaqueductal gray then send projections to the hypothalamus, limbic system nuclei, PF, and CM nucleus.

The body is also capable of suppressing pain signals from these ascending pathways. Opioid receptors are found at various sites at the level of the spinal cord and in structures such as the periaqueductal gray, nucleus raphe magnus, dorsal raphe, rostral ventral medulla, caudate nucleus, septal nucleus, hypothalamus, habenula, and hippocampus. At the level of the spinal cord, these G-protein–coupled receptors are found on the presynaptic ends of nociceptive neurons of Rexed layers IV through VII. Beta-endorphins, enkephalins, and dynorphins serve as ligands that activate these receptors and cause cell hyperpolarization via activating potassium channels and blocking calcium influx—the subsequent inhibition of substance P results in blocked pain transmission. The descending pain suppression pathway is a circuit composed of the periaqueductal gray, locus coeruleus, nucleus raphe magnus, and nucleus reticularis gigantocellularis. The periaqueductal gray and its associated structures modulate the body's response to stress, especially pain, via opioid receptors. It suppresses information carried via C-fibers, not A-delta fibers, by inhibiting local GABAergic interneurons.

Clinical Significance

Complex regional pain syndrome (CRPS) is a neurological condition in which one experiences severe, chronic pain alongside sensory, autonomic, motor, and trophic impairment, primarily affecting the limbs. Type-I CRPS is not limited to a single nerve; therefore, pain is felt diffusely with an emphasis on the distal aspect of the extremity. It is characterized by pain, allodynia, abnormal sudomotor activity, and blood flow. In contrast, type-II CRPS is limited to a few nerves and their branches. It is associated with burning pain, allodynia, and hyperpathia. The pain is not correlated with any evidence of nerve damage, but minor injuries, trauma, and surgery can induce it. While the exact pathophysiology of CRPS is unclear, it is currently hypothesized that an exaggerated response to inflammation triggers it. The release of proinflammatory factors after tissue injury leads to the cardinal features of inflammation (redness, increased heat, swelling, pain, and loss of function), which also correspond to the features of CRPS. Persistent inflammation is also accompanied by a decreased threshold for pain and an enhanced responsiveness to pain. Neuropeptides, such as substance P, bradykinin, and glutamate, mediate the increased activity of secondary nociceptive neurons in the pain circuitry, leading to enhanced pain perception. In the chronic phase of CRPS, increased adrenergic receptors on nociceptive neurons demonstrate that the increased sympathetic drive mediates the continued perception of pain. Currently, physical and occupational therapy is considered the first-line therapy for managing CRPS.