Stimulatory Regulation of Nociceptive Pain

Nociception is the sensory detection, transduction, and neural transmission of noxious stimuli, which affect “high-threshold” primary afferent sensory neurons called nociceptors located in superficial soma (skin, mucosa), deep soma (muscles, bone) and viscera (organs).13 Nociceptors require intense, actually or potentially tissue damaging stimuli to depolarize their terminals. Intense mechanical stimuli activate mechanoreceptors, while intense heat or cold activate thermal nociceptors.

However, chemical activators (e.g., protons, ATP, bradykinin), which directly excite primary afferent sensory neurons, are the most important stimuli.14 Other chemicals, known as sensitizing agents (e.g., prostaglandin E2), increase the sensitivity of nociceptors to chemical activators.15 Protons, from low extracellular pH associated with ischemia and inflammation, activate acid sensitive ions channels (ASICs) and transient receptor potential vanilloid ion channels (TRPV1, TRPV2).

High extracellular ATP levels associated with cell injury activate P2X ligand-gated channels and P2Y Gs-protein-coupled receptors. Bradykinins, associated with tissue damage and inflammation, activate Gs-protein-coupled bradykinin B1 and B2 receptors.16 B1 receptors are expressed in response to bacterial lipopolysaccharides and inflammatory cytokines.17,18 Activation of B2 receptors, which are expressed constitutionally in neurons, promotes the synthesis of prostaglandin E2 (PGE2).

Activation of peripheral sensory terminals by noxious stimuli leads to intracellular sodium and calcium ion influx and neuronal depolarization (Figure 1). If the threshold for activation of voltage-sensitive sodium channels is reached, neuronal depolarization leads to action potential generation. There are six types of voltage-gated sodium channels, four of which are expressed uniquely in primary afferent sensory fibers and two of these only respond to high-threshold peripheral stimuli.

Figure 1. Activation of peripheral sensory terminals.

In the trigeminal-dorsal root complex, incoming action potentials activate pre-synaptic voltage-sensitive calcium channels, which lead to calcium influx, synaptic release of glutamate, and subsequent action potential generation in secondary afferent neurons (Figure 2). Secondary neurons travel to the thalamus and synapse with tertiary afferent neurons, which project to the somatosensory cortex and limbic system responsible for the localization and emotional aspects of pain, respectively.19,20

Figure 2. Neurotransmission in the trigeminal nucleus.

There are three groups of sensory fibers: groups A (A-α, A-β, A-γ, and A-δ), B, and C. Fibers in groups A and B are myelinated. C fibers are nonmyelinated. Nociceptive information is conducted by A-δ and C fibers. A-δ fibers conduct information rapidly, i.e., first pain, which is perceived as sharp, bright, well-localized pain, but not particularly persistent. C fibers conduct information slowly, i.e., second pain, which is perceived as dull, throbbing, burning, diffuse, and persistent.