Mechanism of Nociception

Nociception or pain perception is the result of sensory detection, transduction, and neural transmission of noxious events to the central nervous system (CNS).6 The initial stimulus affects “high-threshold” primary afferent sensory neurons, i.e., free nerve endings called nociceptors located in superficial soma (skin, mucosa), deep soma (muscles, bone) and viscera (organs). 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.7 Other chemicals, known as sensitizing agents (e.g., prostaglandin E2), increase the sensitivity of nociceptors to chemical activators.8 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.9 B1 receptors are expressed in response to bacterial lipopolysaccharides and inflammatory cytokines.10,11 Activation of B2 receptors, which are expressed constitutionally in neurons, promotes the synthesis of prostaglandin E2 (PGE2).10,11

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.12-14

Figure 1. Activation of Peripheral Sensory Terminals.

Image: Activation of peripheral sensory terminals.

Incoming action potentials in the trigeminal/dorsal root complex activate pre-synaptic voltage-sensitive calcium channels, which leads to synaptic release of glutamate, and subsequent action potential generation in secondary neurons. Secondary afferent neurons project to the thalamus and synapse with tertiary afferent neurons. Tertiary afferent neurons project to the somatosensory cortex responsible for the localization of pain; and to the limbic system responsible for the emotional aspects of pain.15,16

There are three groups of sensory fibers: groups A (A-α, A-β, A-γ, and A-δ), B, and C. Nociceptive information is conducted by myelinated A-δ and nonmyelinated C sensory neurons. Information via A-δ fibers arrives rapidly; i.e., first pain, which is perceived as sharp, bright, well-localized pain not particularly persistent, but immediately associated with tissue injury. Information via C fibers arrives slowly, i.e., second pain, which is perceived as dull, throbbing, burning, diffuse, and persistent.