Nociceptor

A nociceptor (from Latin nocere 'to harm or hurt'; lit. 'pain receptor') is a sensory neuron that responds to damaging or potentially damaging stimuli by sending "possible threat" signals to the spinal cord and the brain. The brain creates the sensation of pain to direct attention to the body part, so the threat can be mitigated; this process is called nociception.

Nociception and pain are usually evoked only by pressures and temperatures that are potentially damaging to tissues. This barrier or threshold contrasts with the more sensitive visual, auditory, olfactory, taste, and somatosensory responses to stimuli. The experience of pain is individualistic and can be suppressed by stress or exacerbated by anticipation. Simple activation of a nociceptor does not always lead to perceived pain, because the latter also depends on the frequency of the action potentials, integration of pre- and postsynaptic signals, and influences from higher or central processes.

Nociceptors were discovered by Charles Scott Sherrington in 1906. In earlier centuries, scientists believed that animals were like mechanical devices that transformed the energy of sensory stimuli into motor responses. Sherrington used many different experiments to demonstrate that different types of stimulation to an afferent nerve fiber's receptive field led to different responses. Some intense stimuli trigger reflex withdrawal, certain autonomic responses, and pain. The specific receptors for these intense stimuli were called nociceptors.

Studies of nociceptors have been conducted on conscious humans as well as surrogate animal models. The process is difficult due to invasive methods that could change the cellular activity of nociceptors being studied, the inability to record from small neuronal structures, and uncertainties in animal model systems as to whether a response should be attributed to pain or some other factor.

In mammals, nociceptors are found in any area of the body that can sense noxious stimuli. External nociceptors are found in tissue such as the skin (cutaneous nociceptors), the corneas, and the mucosa. Internal nociceptors are found in a variety of organs, such as the muscles, the joints, the bladder, the visceral organs, and the digestive tract. The cell bodies of these neurons are located in either the dorsal root ganglia or the trigeminal ganglia. The trigeminal ganglia are specialized nerves for the face, whereas the dorsal root ganglia are associated with the rest of the body. The axons extend into the peripheral nervous system and terminate in branches to form receptive fields.

Nociceptors are usually electrically silent when not stimulated. The peripheral terminal of the mature nociceptor is where the noxious stimuli are detected and transduced into electrical energy. When the electrical energy reaches a threshold value, an action potential is induced and driven towards the central nervous system (CNS). This leads to the train of events that allows for the conscious awareness of pain. The sensory specificity of nociceptors is established by the high threshold only to particular features of stimuli. Only when the high threshold has been reached by either chemical, thermal, or mechanical environments are the nociceptors triggered.

In terms of their conduction velocity, nociceptors come in two groups. The Aδ fiber axons are myelinated and can allow an action potential to travel towards the CNS at speeds from 5 to 30 meters/second. The C fiber axons conduct more slowly at speeds from 0.4 to 2 meters/second due to their smaller diameters and little or no myelination of their axon. As a result, pain comes in two phases: an initial extremely sharp pain associated with the Aδ fibers and a second, more prolonged and slightly less intense feeling of pain from the C fibers. Massive or prolonged input to a C fiber results in a progressive build up in the dorsal horn of the spinal cord; this phenomenon called wind-up is similar to tetanus in muscles. Wind-up increases the probability of greater sensitivity to pain.

Thermal nociceptors are activated by noxious heat or cold at various temperatures. There are specific nociceptor transducers that are responsible for how and if the specific nerve ending responds to the thermal stimulus. The first to be discovered was TRPV1, and it has a threshold that coincides with the heat pain temperature of 43 °C. Other temperature in the warm–hot range is mediated by more than one TRP channel. Each of these channels express a particular C-terminal domain that corresponds to the warm–hot sensitivity. The interactions between all these channels and how the temperature level is determined to be above the pain threshold are unknown at this time. The cool stimuli are sensed by TRPM8 channels. Its C-terminal domain differs from the heat sensitive TRPs. Although this channel corresponds to cool stimuli, it is still unknown whether it also contributes in the detection of intense cold. An interesting finding related to cold stimuli is that tactile sensibility and motor function deteriorate while pain perception persists.