Unmyelinated axons occur in almost all tissues, and the sensory ones generally mediate the senses of pain and temperature. The sensory receptors that respond to injurious stimuli are called nociceptors.

Nociception involves two groups of afferent fibres:

• A-delta fibres which cause a pricking pain (fast pain)
• C-fibres which cause an intense aching pain that is emotionally draining (slow pain).

These terms ‘slow’ and ‘fast’ point to the speed of conduction of these two fibre groups, and the time take for impulses to travel into the CNS. Both induce flexor and autonomic reflexes.

Nociceptors respond to injurious stimuli caused by

• Intense forces and pressures
• High temperatures (<45 degrees C)
• Strong chemical solutions
• Cold
• the presence of algesic agents such as bradykinin and sone prostaglandins

The mechanism by which nociceptors respond to these intense stimuli requires membrane proteins called TRPV receptors that excite action potentials in the axons by allowing non-specific ion currents to depolarise the free nerve endings..

Transient Receptor Potential Vanilloid channels are a super-family of transient receptor potential (TRP) ion channels, that are selective for calcium and magnesium over sodium ions. Members of the family respond to noxious heat, cold, acid, osmolality and capsaicin, a vanilloid molecule derived from hot red peppers.

Nociceptors respond to high intensity stimuli.  Take temperature as an example (see diagram opposite). The thermoreceptor responds to small increases in temperature BUT the nociceptor only responds to temperatures above 44-46 degrees C – the temperature at which pain can occur and there is evidence of skin injury.

Nociceptive sensory neurones have many branches within the skin and some innervate blood vessels.

These branches liberate chemicals that cause vasodilatation and increase capillary permeability.

The "axon reflex" is not a proper reflex because there are no synapses in the neural pathway, but noxious stimulation induces redness and tissue swelling because of sensory impulses that release mediators in the blood vessel and cause the "flare". The flare occurs because of vasodilatation (redness) and increased permeability that results in the movement of plama proteins into the extracellular fluid.

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Sensitization of unmyelinated afferent fibres

Sensitization occurs when an unmyelinated nerve sensory ending that is normally responsive only to extreme forces and movements, becomes sensitive to normal forces and movements.

One example of sensitization is inflammation: normally nociceptive nerve endings respond only to extreme forces and movements, but, once sensitized, they become much more sensitive and respond to normal movements. In both circumstances the messages they carry give rise to pain.

Inflammation

In an inflamed joint, a small movement can give rise to pain. IN this condition, the unmyelinated nerve endings can become sensitized, and instead of responding only to large forces and movements, become very sensitive to any movement- because these nerve endings are affected by chemicals produced within damaged tissues, such as

• Bradykinin, and
• Prostaglandins

Chemicals with the ability to sensitize the nociceptive nerve endings are known as Endogenous Algesic Agents.

Some of the common over-the-counter analgesic drugs act by interfering with the production or action of these agents.

Endogenous Algesic Agents

Bradykinin is a peptide produced by enzymes released from damaged cells acting on a plasma protein, and is found in fluid in inflamed joints. The effects of Bradykinin include :

• vasodilatation
• local oedema (extravasation of plasma proteins)
• pain
  

they induce vasodilatation
they increase capillary permeability to plasma proteins, - causing local oedema
they are all Algesic Agents

Neuropeptides in unmyelinated nerves.

Fine unmyelinated afferents contain neuropeptides which can sensitize sensory endings when they are released. These peptides attract cells of the immune system, cause vasodilatation and increased capillary permeability. These neuropeptides include:

• Substance P
• Calcitonin gene-related peptide (CGRP)
  

Analgesic drugs

Some analgesic drugs act at peripheral nerve endings. Common analgesic drugs that are bought over the counter act by interfering with the production of prostaglandins that act on the peripheral terminals of unmyelinated axons.

These drugs include:

• hydrocortisone and other more powerful corticosteroids (glucocorticoids)
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including Indomethacin and Ibuprofen
• Aspirin and Paracetamol

Central Pathways for Pain and Temperature

Spinothalamic tract

This pathway is concerned with pain and temperature. The small myelinated and unmyelinated (A-delta and C) axons of dorsal root ganglion cells synapse in the dorsal horn.

The axons of these second-order neurones cross to the opposite side of the cord within a few segments, then pass rostrally and directly to the posterior group of nuclei in the thalamus, without synapsing en route.

The axons of third order neurones in the pathway project from the ventral posterior thalamus to areas of the cortex including the second somatosensory area SII.

The antero-lateral white matter of the cord contains not only the spino-thalamic tract, but other pathways arising from the dorsal horn and known to carry nociceptive signals.

Some of these axons project to the reticular formation and the midbrain, and together they form the Anterolateral System.

Some axons in the pain pathway project to the reticular formation (spino-reticular fibres) and to the periaqueductal grey matter of the midbrain.

It is believed that the snapses in the dorsal horn can modulate the pain message. This can happen through to main mechanisms:

• interactions between innocuous and nocicptive inputs to the dorsal horn (the 'Gate' Theory), and
• descending pathways that terminate in the dorsal horn.

Spinothalamic Tract
Spino-Reticular Tract
Structure of the Dorsal Horn
Gate Theory
Referred Pain
Descending Influences on the Dorsal Horn

The Gate Theory suggests that the perception of pain depends on the balance of large and small fibre activity entering the dorsal horn, and that large myelinated fibre activity can reduce the onward transmission of nociceptive signals carried by unmyelinated axons.

There is now a lot of evidence that the pain signal can be modulated in the dorsal horn.

1. Stimulation of large afferent fibres, by rubbing the skin, or by electrical stimulation of the skin (TENS) can reduce the perception of pain, and it is a common behaviour to rub an area of skin that has recently been hit by a hard object.
2. Dorsal column stimulation has been performed in humans using implanted electrodes; these stimulate a collateral of the large afferent neurones, and the impulse that passes antidromically down the cord appears to be able to reduce the perception of pain in ptients with chronic pain conditions. The suggestion is that this mechanism is identical to tht proposed in the Gate Theory.

Descending pathways are known to terminate in the dorsal horn and modulate nociceptive transmission at that site. These pathways originate in the brainstem reticular formation and the periaqueductal grey matter of the midbrain. Many use amines as transmitters.

These descending pathways are part of the  endogenous pain suppression system that causes a reduction in pain perception when an additional noxious stimulus is applied. This is thought to be the basis of counterirritation phenomena, in which a severe stimulus, such as heat, is applied to the skin and can be effective in reducing other pains. The process of 'cupping' - applying heated glass cups to the skin was an ancient method of pain relief that depends on this system. The heat required was usually sufficient to cause blisters.

More information on descending pathways form the reticular formation involved in pain modulation can be found here.

Acupuncture analgesia is also believed to work by activating inhibitory descending paths to the dorsal horn. Acupuncture analgeis is blocked by naloxone, and seems to depend on the release of enkephalins in the spinal cord.

Chronic Pain

Chronic Pain is associated with neuroplastic changes in nociceptors and in the dorsal horn. The link below discusses the mechanisms involved in persistent pain.

Phantom Limbs are a sensory phenomenon that follows amputations and spinal cord injury. The mechanisms underlying these sensations are discussed in the link below.

Sensitization of nociceptors
Types of Voltage-gated Sodium Channels in Nociceptors
Neuroplastic changes in the dorsal horn

Amputations
Spinal Cord Injury
Neuroplasticity in the Cortex

Thermoreceptors

Thermoreceptors are usually unmyelinated afferents that are sensitive to the normal range of temperatures found on skin. One type of mechanoreceptor, the Type II slowly adapting mechanoreceptor, is also involved sensitive to the temperature of skin, and some authors have suggested it is involved in temperature sensation. However these receptors are very sensitive to skin stretch, so it seems unlikely tht these are the main thermoreceptors in skin..

Thermoreceptors are particularly evident in the scrotum, and temperature changes to this area induce the cremasteric reflex, which controls the position of the testis, so as to keep it at an appropriate temperature to preserve fertility.

Thermoreceptors in skin can influence blood flow and sweating.

The main thermoreceptors involved in the regulation of body temperature are in the hypothalamus.