The first step in the complex mechanism of pain processing is the transduction of a noxious stimulus (nociception) by specialized nerves (nociceptors). Nociceptors are found in most organs and tissues in the body and are activated by either a noxious mechanical (touch or pressure), thermal (hot or cold), or chemical (endogenous or exogenous) stimulus. The term “noxious” is applied to nociceptive stimuli because nociceptors are activated in response to strong stimuli that fall in the tissue- damaging range, whereas non-nociceptive mechanoreceptors, thermoreceptors, and chemoreceptors respond to milder
stimuli that fall in a range below the tissue-damaging level. In addition to exogenous chemicals that stimulate nociceptors, some endogenous chemicals have been identified that can activate nociceptors, including potassium, bradykinin, serotonin, histamine, prostaglandins, and others. Pain physiology appears to exert different mechanisms in different sections of the central nervous system. These mechanisms are captured under two large headings that comprehensively describe the overall pathways of nociceptive activations and transmission and the descending pathway of pain modulation.
PAIN TRANSMISSION—ASCENDING PAIN PATHWAYS
Spinal dorsal horn When a noxious stimulus is transduced by a nociceptor, a signal is generated that is transmitted as an electrical action potential along small diameter A-delta (myelinated, fast transmission, sharp or pricking first pain) and C (unmyelinated, slow transmission, dull or burning second pain) primary afferent nerve fibers to the gray matter of the spinal cord. On cross-section, the spinal gray matter forms a butterfly shape and can be divided into 10 laminae, or layers, which are numbered I through IX, from dorsal to ventral, with X surrounding the central canal. Pain processing occurs predominantly in laminae I, II, and V. The primary afferent fibers enter the spinal cord in the dorsolateral aspect of the gray matter (the dorsal horn) through the dorsal root. Upon entering the dorsal horn, the primary afferents bifurcate in a “T” pattern and travel two to three spinal segments within Lissauer’s tract in both the rostral (toward the nose) and caudal (toward the tail) directions. As the primary afferents travel in Lissauer’s tract, they send collateral projections to the gray matter along the entire four- to six-segment length and transmit the pain signal over a broad area of the spinal cord rather than to a discrete location. This is important in the case of spinal pathologies, such as a lesion, which could block the signal if it is transmitted to a discrete location within the area of pathology. In the dorsal horn, the primary afferent fibers synapse (connect), either directly or indirectly (via interneurons), with second- order projection neurons and convey the nociceptive message through the release of a variety of neurotransmitters, such as the excitatory amino acid glutamate or the peptide substance P. After the nociceptive signal has been received in the dorsal horn, the information is transmitted to higher centers in the CNS by projection neurons. Ascending tracts The projection neurons transmit the nociceptive signal rostrally along the ascending pathways in the spinal cord to various supraspinal structures in the brainstem and diencephalon, including the medullary reticular formation, periaqueductal gray, parabrachial region, hypothalamus, thalamus, and various limbic structures. The function of the ascending pathways is simply the transmission of nociceptive information. Within the supraspinal target structures of the ascending pathways, third-order neurons further process the nociceptive signal and transmit it to cortical and limbic structures, where the signal is interpreted as pain. The organization of and the neuroanatomy within the ascending pain pathways are quite complex. The most prominent and well-described of the ascending pathways is the spinothalamic tract (STT—spinal cord to thalamus), which is thought to transmit sensations of pain, temperature, and touch. The majority of the projection neurons that travel in the STT originate in the superficial laminae I and II and deeper lamina V of the spinal dorsal horn (Al-Chalabi et al., 2022). Descending modulation of nociception The descending modulation of nociception is the idea that pain undergoes a modulatory effect from the higher areas of the central nervous system. This idea, first proposed by Head
Before ascending, the STT neurons decussate (cross midline) through the ventral white commissure (junction between two parts) to the opposite ventrolateral quadrant of the spinal cord white matter, where they ascend in the ventrolateral funiculus (VLF—bundle of nerve fibers) to the thalamus. A second prominent ascending pathway that is involved in pain transmission is the spinomesencephalic tract (SMT—spinal cord to mesencephalon), which originates in laminae I, II, and V of the spinal dorsal horn, decussates, and also travels in the VLF to the mesencephalon (also known as the midbrain ). Within the midbrain, the neurons in the SMT terminate in several areas, such as the periaqueductal gray (PAG) and nucleus cuneiforms, among others. A third tract that has also been shown to convey nociceptive information is the spino-reticular tract (SRT—spinal cord to reticular formation), which terminates in the reticular formation of the medulla. Though each ascending tract has a primary target structure, they also send collateral projections to other areas of the brainstem as they pass through. When the projections from the spinal cord reach their targets, they synapse with third-order neurons that serve as relays and project to other regions within the brainstem, diencephalons, and forebrain. While the three pathways already described are thought to be the predominant pathways involved in pain transmission, they do not constitute a complete list of all ascending sensory pathways. Thalamus A systematic review of multiple scientific publications on the role of the thalamus in the physiology of pain identified this biological structure as the major supraspinal relay structure for the integration and transfer of ascending nociceptive stimuli to the cerebral cortex. In essence, the thalamus does not only transmit inputs from the spinothalamic tract (STT), but it also receives input from collateral projections sent out of the other ascending tracts that carry nociceptive information. Within the thalamus, nociceptive information regarding the type, temporal pattern intensity, and topographic localization of the pain is encoded before sending the information onward to limbic structures and cortical sites. Cerebral cortex Finally, the nociceptive signal reaches the cerebral cortex, where it is integrated and undergoes cognitive and emotional interpretation as stemming from a painful stimulus. The nociceptive signal is transmitted from the thalamus to a variety of cortical sites: the somatosensory S1 area and S2 area, the insular cortex, the anterior cingulate cortex, and the medial prefrontal cortex. Within these cortical regions, there is a complex network of interconnections that includes the thalamus and limbic structures. This network of cortical structures is responsible for the sensory-discriminative (perception of the intensity, location, duration, temporal pattern, and quality of noxious stimuli) and motivational-affective (relationship between pain and mood, attention, coping, tolerance, and rationalization) components of the pain experience.
and Holmes, has now received huge attention with different clinical researchers now designed to further investigate pain modulation and perception using Head and Holmes’s models.
Book Code: PYFL4024
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