Pain is the human body’s subjective experience in response to actual or potential tissue damage.¹ This unpleasant response has a protective role in alerting the body to potential danger and providing a means for self-preservation.² Pain can be classified as acute or chronic. While definitions may vary, acute pain usually lasts <3-6 months and is limited in duration. Acute pain typically has a sudden onset caused by noxious stimuli and follows some form of injury to the body. This type of pain resolves as soon as the initial injury heals. Acute pain can result from surgery, illness, or specific injuries to the body.

Noxious stimuli from the environment can lead to the activation of various nociceptors. Activation of these nociceptors then causes the transmission of a signal to the spinal cord’s dorsal horn by neurons. At this location, the signal may be modulated before being sent to the central nervous system and further modified by various neurotransmitters. The result is the perception of pain by the brain.³

Knowledge of the basic anatomy, physiology, and neurotransmitters involved in the perception of acute pain allows for the proper diagnosis, treatment of, and resolution of acute pain. Additionally, understanding these mechanisms is valuable in guiding the development of new treatment interventions by targeting various parts of the pain pathway.³

Pain is the result of an activated pathway that is signaled by noxious stimuli and nociceptors. Nociceptors are receptors that occur throughout the body to sense noxious stimuli. The nociceptors then activate and transmit action potentials by nerves that connect to the spinal cord. The processing of potentially dangerous stimuli to the body by the nociceptors and nerve pathways is performed by the central nervous system and peripheral nervous system. This is referred to as the concept of nociception and can communicate noxious mechanical, thermal, or chemical stimulation stimuli.

The perception and interpretation of pain is described as a four-part process: transduction, transmission, modulation, perception.⁴ The transduction of pain is the stimulation of the nociceptor to the activation of the sensory nerve ending. The transmission of pain refers to the pain signal transmitted along the nerve and spinal cord pathway from the nociceptor toward
the brain. The modulation process describes the alteration of the pain signal as it ascends the spinal cord and through the brain. A contextualization of the noxious stimuli and circumstances may alter the pain signal through this modulation process. Finally, the perception of pain is the reception of the brain’s pain signal and results in an understanding of the message and a concurrent physical or emotional response.

Pain signals travel as action potential impulses along a nociceptive pathway that courses the peripheral nerve, spinal cord, and brain.⁵ A voltage-gated sodium channel mediates the conduction of these pain signals along an afferent axon. Each of the primary afferent neurons terminates in the dorsal horn of the spinal cord. At this location, they activate second-order pain-transmitting cells in the dorsal horn of the gray matter. The signal then decussates or crosses over to the other side of the spinal cord, traveling up the spinothalamic tract toward the thalamus and brain. The spinothalamic tract is the main pathway that pain signals travel along the spinal cord.

Nociceptors throughout the body give rise to two different types of pain fibers: unmyelinated C fibers and A delta (Aδ) fibers.⁴ Unmyelinated C fibers are smaller in diameter, 0.4-1.2 mm, and conduct at a slow velocity, 0.5-2.0 m/s.⁶ Slower than the Aδ fibers, C fibers transmit aching, imprecise localization, burning pain.⁷ Responsible for about 70% of pain transmission, the C fibers are much more numerous than Aδ fibers. Aδ fibers are thicker myelinated fibers with a fast conduction velocity.⁸ The Aδ fibers transmit the exact localization of sharp, stinging pain.⁴

The nociceptors activate action potentials based on a variety of substances that are released from damaged tissue. In response to mechanical, thermal, or chemical stimuli, the following substances are released: globulin and protein kinases, arachidonic acid, histamine, nerve growth factor, substance P, calcitonin gene-related peptide, potassium, serotonin, acetylcholine, acidic solution, ATP, and lactic acid.⁴ Globulin and protein kinases may be released to cause severe pain in damaged tissue. Arachidonic acid is also released in response to damaged tissue. Through a biochemical pathway, metabolism to prostaglandins results in a G protein-mediated protein kinase A cascade. Aspirin works to block the arachidonic acid from forming prostaglandins. Histamine release from tissue damage also activates nociceptors to activate pain action potentials. Tissue damage and inflammation may also lead to the release of substance P and calcitonin gene-related peptide. In addition to the activation of nociceptors, they also cause vasodilation and, subsequently, tissue edema. Tissue damage also results in potassium release and a decrease in tissue pH. Serotonin, acetylcholine, and ATP are also released during tissue damage and cause nociceptors to become excited. Finally, muscle spasms and lactic acid can cause nociceptor activation during hyperactive muscle use or restricted blood flow to a muscle.

After nociceptors respond to noxious stimuli, an action potential transmits a pain signal to the central nervous system. Within the central nervous system’s gray matter, there is a system of ten layers called the Rexed laminae.⁵ The nociceptive axons enter the spinal cord through the dorsal roots and project toward the dorsal horn. The signals then branch, forming the Lissauer tract, which branches toward ascending and descending spinal cord tracts before entering the dorsal horn. Within the dorsal horn, the pain neurons are organized into different Rexed laminae. Rexed laminae I is called the marginal zone and relays pain and temperature sensation. Rexed laminae II are called the substantia gelatinosa and relays pain, temperature, and light touch sensation. Rexed laminae III/IV are the nucleus proprius and relays mechanical and temperature sensation to the brain. The first-order neurons of the spinothalamic tract synapse in these areas.

The spinothalamic pathways include the anterolateral spinothalamic, spinoreticular, and spinomesencephalic tracts. Fast (Aδ) and slow (C) nerve fibers constitute two main pathways within the spinothalamic tract. The fast- and slow-conducting pathways are also known as the neospinothalamic and paleospinothalamic tracts⁹ (see Fig. 1.1).

Primary (first-order neuron) nociceptive afferents carry information regarding pain and temperature from the periphery to the spinal cord. These primary afferents are fast-conducting myelinated Aδ fibers or slow-conducting unmyelinated C fibers. Fast (˜20 m/s) Aδ fibers transmit information about sharp, pricking, or well-localized pain. Slow (˜0.5-2 m/s) C fibers transmit information about crude touch, temperature, chemical, or poorly localized pain. Both fast and slow primary nociceptive afferents synapse in the dorsal horn of the spinal cord. The dorsal horn is divided into six cytologically distinct areas known as Rexed lamina.¹⁰ Lamina I contains the secondary (second-order) neurons of the marginal zone nucleus. Lamina II contains the secondary neurons of the substantia gelatinosa. Lamina III & IV contain tertiary (third-order) neurons of the nucleus proprius.

Fast Aδ nociceptive afferents synapse in or near lamina I (marginal zone); secondary afferent axons arising from the marginal zone neurons cross the anterior white commissure and ascend in the contralateral lateral (mostly) and anterior spinothalamic tract and synapse on
tertiary neurons located in the ventral posterolateral nucleus of the thalamus. The tertiary axons projecting from the ventral posterolateral nucleus then travel to the primary somatosensory cortex in the postcentral gyrus of the parietal lobe.

Slow primary C nociceptive afferents synapse in dorsal horn lamina II (substantia gelatinosa). Second-order axons then project from the substantia gelatinosa neurons a short distance to synapse in or near the ipsilateral nucleus proprius of lamina III & IV. Tertiary afferent axons then project from the nucleus proprius and cross the anterior white commissure to enter the contralateral anterior (mainly) and lateral spinothalamic tracts. Tertiary afferents from the nucleus proprius that comprise the spinoreticular tract exit to terminate in the medullary and pontine reticular formation. The reticular formation is thought to be responsible for levels of attention and consciousness and may play a role in modulating the response to pain.¹¹ Many of the tertiary afferents from the nucleus proprius that comprise the spinomesencephalic tract leave the spinothalamic tract to terminate in the midbrain periaqueductal gray (PAG) zone in the rostral pons and lower midbrain. The spinomesencephalic tract is thought to play an important role in the inhibition of pain. When PAG cells are activated, they are thought to act as a pain suppression system that releases endogenous opioids and other neurotransmitters to inhibit pain transmission at the spinal cord level (substantia gelatinosa).¹² The remaining tertiary afferents of the spinomesencephalic tract continue to the thalamus, where they synapse in either the centromedial nuclei or the nucleus parafascicularis within the intralaminar nuclei of the thalamus. The 4° (fourth-order neuron) afferent axons of the intralaminar nuclei then project diffusely throughout the cerebral cortex, hence their association with poorly localized sensory pain.

The spinal trigeminal pathway of the brain is an analog to the spinothalamic tract of the cord. The spinal trigeminal pathway conveys sensory information about pain, temperature, and crude touch from the head and neck. Primary nociceptive afferents carried by cranial nerves V, VII, IX, and X join the spinotrigeminal tract in the mid pons, caudal pons, upper medulla, and mid medulla, respectively. The spinotrigeminal tract receives these primary afferents from the cranial nerves during its caudal course in the brainstem, terminating in the spinal trigeminal nucleus. The spinal trigeminal nucleus extends throughout the brainstem (midbrain, pons, and medulla) and into the high cervical spinal cord. Most secondary afferents of the spinal trigeminal nucleus decussate immediately and travel contralateral and rostral in the brainstem toward the thalamus in the nerve tract known as the ventral trigeminothalamic tract. As it courses through the brainstem to the thalamus, secondary afferents of the ventral trigeminothalamic tract branch and, together with spinoreticular afferents ascending from the spinal cord, terminate in the medullary and pontine reticular formations. Remaining secondary afferents in the ventral trigeminothalamic tract then terminate in the ventral posteromedial and intralaminar nuclei of the thalamus. Tertiary afferents then project from the ventral posteromedial nucleus of the thalamus and terminate in the ventrolateral area of the postcentral gyrus. The tertiary afferents from the thalamus’s intralaminar nucleus terminate diffusely in multiple cortical regions¹³ (see Fig. 1.2).

Wide dynamic range neurons are found in and comprise many neurons located in the spinal cord’s dorsal horn. They may be projection neurons or interneurons for polysynaptic responses. They receive input from a broad range of sensory modalities (Aδ, C, nonnoxious A-fiber) and continuously process environmental (ie, nociceptors/proprioception) and internal (ie, interneurons/descending brainstem) signals. This somesthetic activity may help to discriminate between varying degrees of nociceptive input. Wide dynamic range neurons possess large receptive fields with both low and high threshold areas. They demonstrate plasticity that allows them to modify their receptive field size. Nociceptive-specific fibers, in contrast, have a smaller receptive field that does not demonstrate plasticity, and they receive inputs only from Aδ and C fibers.¹⁴

Pain perception is not limited to one specific area of the brain. It involves multiple neural structures including nociceptors, spinothalamic tracts, somatosensory cortex, thalamic projections (sensory relay), prefrontal cortex (planning of complex behavior and decision making), cingulate cortex (provides an emotional description of pain and helps to coordinate response), and insula cortex (links emotion to action). It can be viewed as a fluid system that may explain why pain experiences are individualized. Chronic pain from nociceptive or nonnociceptive factors can cause prolonged pain matrix activation.¹⁵ Second-order neurons are not nociceptive specific, while third-order neurons associated with orbitofrontal and limbic systems modify the pain experience based upon various factors, including beliefs, emotions, and expectations.¹⁶ This multifactorial and unique individual interpretation of nociceptive stimuli is termed the pain matrix.

Both ascending and descending pathways can modulate nociceptive signals. Opiate receptors exist at the spinal cord’s dorsal horn and binding to these receptors causes hyperpolarization of these neurons. This results in inhibition of firing and preventing the release of substance P, thus blocking ascending nociceptive signal transmission.¹⁷

Together, the PAG and rostral ventromedial medulla (RVM) form a regulatory loop controlling the descending pain modulation pathway. This regulatory loop may facilitate or inhibit pain, depending on which cells in the system are activated. The PAG is an area of gray matter in the midbrain surrounding the cerebral aqueduct. It receives input from various limbic system regions and plays a significant role in controlling descending pain modulation. The PAG projects to the serotonergic neurons of the RVM and locus coeruleus (LC), a part of the brain involved in physiological responses to stress. The RVM includes the nucleus raphe magnus (a member of the rostral group of raphe nuclei, the primary location for serotonin production within the brain), and other adjacent nuclei. The RVM receives input from the hypothalamus, amygdala, insula, and PAG. RVM cells project to the spinal cord’s dorsal horn, the preganglionic sympathetic neurons, and the central canal.¹⁸ By utilizing these connections, the RVM works in conjunction with the PAG to act as the primary control center modulating descending pathways of nociceptive transmission.¹⁹