Nociceptors

What activates nociceptors?

Nociceptors are activated by three kinds of noxious stimulus: mechanical, thermal, and chemical. Chemicals that activate nociceptors include histamine, bradykinin, acids, acetylcholine, and potassium ions. Substance P and prostaglandins raise nociceptor sensitivity by partially depolarising the neuron, mainly by modulating ion channels and intracellular signaling. They lower the activation threshold without firing an action potential on their own.

Nociceptors also respond to high-intensity pressure or sharp objects, to extreme heat (>45°C), and to noxious cold (<15°C). These stimuli open specific ion channels in the nerve ending: TRPV1 opens to heat and capsaicin, TRPM8 opens to cold and menthol. TRPA1, the channel for irritant chemicals such as mustard oil, has also been proposed as a noxious-cold sensor, though its role in cold detection is still debated.

Pain pathway

Pain travels through a three-neuron pathway, transmitting signals from the periphery to the brain's cerebral cortex. The first-order neurons -the nociceptors- detect noxious stimuli and their central branches in the dorsal horn of the spinal cord make synapses with the second-order neurons. The second-order neurons cross (decussate) to the contralateral side via the spinothalamic tract, and project to the thalamus. In the thalamus, signals are relayed to third-order neurons to eventually be transmitted to the somatosensory cortex, where pain perception is localized and interpreted.

Aδ fibers

Primary pain, triggered by mechanical and thermal stimuli, is mediated by Aδ fibers. Aδ fibers have myelinated axons with a diameter ranging from 2 to 5 μm and a conduction velocity of up to 30 m/s. They are primarily responsible for transmitting intense short-term stimuli and offer precise localization of pain due to their small receptive fields.

Type I Aδ fibers are primarily responsible for the transmission of mechanical signals and are capable of functioning at temperatures exceeding 50°C.

Type II Aδ fibers are predominantly involved in the transmission of thermal signals, exhibiting higher mechanical thresholds and lower temperature thresholds.

C fibers

Conversely, secondary pain is transmitted via C fibers which are activated by all three stimulus modalities (mechanical, thermal, and chemical), and are, thus, considered polymodal. Type C fibers are unmyelinated, have a small diameter of less than 2 μm, and exhibit a relatively slow conduction velocity, typically less than 2 m/s. These fibers play a crucial role in transmitting sensations such as dull pain and prolonged burning sensations. Their large receptive fields result in less precise pain localization.

Type C fibers fall into two subgroups based on the neuropeptides they express: substance P and calcitonin gene-related peptide (CGRP). Nociceptors that express these molecules are called peptidergic; those that do not are non-peptidergic. The receptors for these neuropeptides are found in many cell types across the peripheral and central nervous systems, and in non-neuronal tissues such as immune and vascular cells. They therefore act beyond the nervous system, in inflammatory and vascular responses.

Pharmaceutical interest in these receptors has grown. CGRP's role in migraine, for example, led to CGRP antagonists that block CGRP signaling to relieve migraine.

Nociceptors transmit pain along two fibre types that differ in speed, structure, and the kind of pain they carry. The table below compares them.

Sensitivity

In contrast to the high sensitivity of receptors in other sensory systems, like the visual or olfactory, nociceptors are activated only to high-threshold stimuli. Τhis ensures greater accuracy between potentially harmful and benign stimuli, so the body learns to prioritize responses to stimuli that threaten tissue integrity. Nociceptors do not respond to light touch or mild temperature changes, distinguishing them from low-threshold mechanoreceptors.

Adaptation

Pain receptors show little, and in many cases, no adaptation. Instead, their activation becomes more intense if the stimulus persists (hyperalgesia) and that reassures that the sensation of pain is felt throughout the stimulus. This property is functionally important because continuous signaling of tissue damage helps ensure appropriate behavioral responses (e.g., withdrawal, protection of the injured area).