Pain, although subjective, can objectively follow the nociceptive pathway beginning from the initial stimulus leading to what we perceive as pain. This phenomenon can be described as nociception, which is defined as “the encoding and processing of noxious stimuli in the nervous system.”¹ Although pain offers our system protection from threats, it can also be unwanted. Stimuli can be chemical, thermal, mechanical, neurogenic, and inflammatory leading to activation of the somatosensory and nociceptive pathways and eventually to the central nervous system (CNS).¹ Pain is an incredibly complex phenomenon, which is why it is tantamount that we explain the neurobiology of acute pain and its intricacies. We will explore the physiologic process from initial stimuli in the periphery from transduction to transmission through the spinal cord to supraspinal levels. We will explain the biology of inflammatory states and acute pain. Furthermore, we will also explain descending pain modulation and the detrimental phenomena of central sensitization involving neuroplasticity with associated hyperalgesia and allodynia.¹,² It is our hope that through this chapter, we can offer our readers a comprehensive understanding of nociceptive pathways to improve treatment for acute pain.¹,³

Nociception is defined as the peripheral process of encoding and processing noxious stimuli. These stimuli activate a nociceptor or peripherally located neuron leading to the eventual realization of pain. The nociceptors are characterized based on the type of stimuli they respond to, with a classification based on whether they respond generally to thermal, mechanical, or chemical stimuli, but can also be classified as polymodal, silent, and mechano-thermal.⁴ The type of receptor is based upon its location, including the skin, joints, and viscera. Nociception is further broken down and characterized by the nerve fiber type with its properties based on the speed of transmission of the axon and diameter of the fiber.⁵

The presence or absence of myelin, which acts as an insulator, is responsible for faster transmission. The degree of myelination can vary. Myelinated fibers act as an insulator that sends a signal that is interrupted at the nodes of Ranvier but has a faster speed of transmission. Unmyelinated fibers provide slower continuous conduction. A-fibers are myelinated, and C-fibers are unmyelinated.⁵ C-fibers are small diameter unmyelinated axons bundled in fascicles, which are surrounded by Schwann cells and support slower conduction velocities, whereas A-fibers are myelinated axons and support faster conduction velocities and mediate
fast onset pain.⁵ A-fibers are further characterized based on motor and sensory properties, breaking down into alpha, beta, delta, and omega, which corresponds to their properties and relating to velocity based on myelination and axon thickness. Alternately, sensory properties are characterized toward which receptors the fibers are related to, characterized as type 1a, type 1b, type II, type III, and type IV.

The process by which a noxious stimulus turns into a painful signal is a multistep process. Peripheral nerve endings are unencapsulated, pseudounipolar, and arise from the dorsal root ganglion (DRG) or trigeminal ganglion with innervation peripherally at the skin and centrally on a second-order neuron.⁵ The process of signal transduction takes place when this noxious stimuli involving free nerve endings (C and A delta fibers) lead to the opening of ion gated channels, which in turn convert it to an electrochemical signal by making changes in membrane potential, then opening additional channels, and the eventual depolarization of the afferent nerve These primary afferents carry this stimulus from the periphery to the CNS where they terminate predominantly in laminae I, II, and V of the dorsal horn on relay neurons and local interneurons.⁴,⁵ The main nociceptive pain transducing channels include acid-sensing ion channels (ASICs), transient receptor potential (TRP), cation channels, and voltagegated sodium channels. ASICs are nonvoltage sensitive, protein-induced sodium channels that detect changes in pH and have been associated with epilepsy, depression, migraines, and neuropathic pain.⁶ TRP channels are a group of channels with different roles and responses to modulators. Examples include TRPV1, which responds by allowing the passage of calcium ions and is potentiated by heat, acidity, and capsaicin, and TRPA1, which is sensitive to thermal, mechanical, and chemical stimuli.⁷ Voltage-gated sodium (Nav) channels play a principal role in the generation of an action potential by being heavily involved in the transformation from transduction to transmission.⁷ Other common voltage-gated channels include calcium and potassium.⁵ The previously mentioned ASIC and TRP depolarize Nav channels leading to the formation of an action potential. Membrane depolarization leads to extracellular sodium ion influx, which in turn causes an increase in membrane potential leading to a threshold whereby an action potential is generated.⁷

Nociceptors are responsive to many different mediators, both inflammatory and noninflammatory, which corresponds to both the receptor type and the location within the body. Common inflammatory mediators include 5-HT, kinins, histamine, nerve growth factors, adenosine triphosphate, PG, glutamate, leukotrienes, nitric oxide, NE, and protons, while noninflammatory mediators include calcitonin gene-related peptide, GABA, opioid peptides, glycine, and cannabinoids.⁶

For noxious stimuli to be perceived, it must first be transduced at the nerve endings in the periphery then transmitted along the nerve axon to the dorsal horn of the spinal cord. Numerous ion channels and G-protein-linked receptors have been identified and thought to play a role in the transduction and transmission of noxious stimuli. One group of ion channels called transient receptor potential ion channels (TRP channels) transduce noxious stimuli by allowing entry of cations leading to depolarization and generation of an action potential that is then transmitted down the axon to the spinal cord. Different types of stimuli (eg, temperature, chemical, and mechanical/intense pressure) activate different subtypes of TRP channels. TRP vanilloid 1 (TRPV1) channel and TRP melastatin 8 (TRPM8) channel respond to heat and cold stimuli, respectively. Several TRP channels are polymodal responding to temperature and chemical stimuli. The following TRP channels also respond to potentially noxious chemical stimuli: TRPV1, the receptor for capsaicin, and TRPM8, the receptor for menthol. Isoflurane’s
pungent odor is transduced by TRP ankyrin 1 (TRPA1) channel, the receptor for mustards and garlic.¹ Two-pore potassium (K2P-KCNK) channels, voltage-gated potassium channels, and voltage-gated sodium channels are other thermotransducers that modulate the response to temperature stimuli. TREK-1 and TRAAK, both part of the KCNK potassium channel family, are found in some C fibers and are proposed to modulate receptor excitability.⁸ Several classes of sodium channels are expressed on sensory neurons; however, Nav 1.7, 1.8, and 1.9 are predominantly found on nociceptors. Mutations within these receptors have been found in painful disorders and insensitivities to pain. Mechanosensory transducers have not been positively identified, although a number of channels have been proposed. Degenerin/epithelial sodium (DEG/ENac) channels; TRPV1, TRPV4, and TRPA1 channels; KCNK channels; and acid-sensitive ion channels (ASICs) are candidate proteins thought to play a role in mechanical hypersensitivity.⁸ Opioid, cannabinoid, GABA_b, and alpha-2 receptors are a few of the G-protein-linked receptors involved in antinociception that work by reducing calcium entry via modulation of calcium channels.¹ Voltage-gated sodium and potassium channels are also involved in signal modulation. Upregulation of the action potential occurs via sodium channels, while downregulation occurs via potassium channels.⁹ A set of action potentials encodes the intensity of the noxious stimulus.⁵ Voltage-gated calcium channels are also involved in transmission of noxious stimuli. A modulatory subunit of the calcium channel is found highly expressed in C fibers especially after nerve injury. This is the target of gabapentin.¹ N- and T-type calcium channels found on C fibers are upregulated after nerve injury in disorders such as diabetic neuropathy.⁸ Once the action potential has reached the dorsal horn, the signal is again transduced to be transmitted to the brain.

During inflammation, cells of the immune system and circulatory system migrate to the sites of injury releasing inflammatory mediators. These mediators include cytokines; chemokines; acute phase proteins; peptides, such as bradykinin; eicosanoids, such as prostaglandins; and vasoactive amines, such as serotonin (Table 2.1). Activated macrophages involved in the upregulation of inflammation secrete proinflammatory cytokines IL-1beta, IL-6, and tumor
necrosis factor (TNF)-alpha (Fig. 2.1). These three cytokines are known to be involved in process of pathologic pain by activating nociceptive sensory receptors. IL-1beta, for example, is expressed in nociceptive DRG neurons and is found to increase PGE₂ and substance P in glial and neuronal cells.¹⁰ Bradykinin, one of the major mediators of pain during inflammation, alters the electrical functions of nociceptor sensory neurons by enhancing their excitability, therefore greatly contributing to pain generation and exacerbation. Bradykinin also electrically sensitizes the pain-mediating nociceptor neurons. It has been hypothesized that bradykinin may augment the depolarization of specific effector ion channels expressed in nociceptor neurons through intracellular signaling via G-protein-coupled receptors. The opening of ion channels TRPV1, TRPA1, and ANO1 is involved in the role as a depolarizing effector in the direct induction of neuronal firing by bradykinin.¹¹