Articular nociceptors are primary afferent neurons that innervate the joints and signal noxious stimuli. In the normal state, articular nociceptors are activated by noxious mechanical stimuli, either mainly, or exclusively. In the presence of inflammation (which includes osteoarthritis) they are sensitised to mechanical stimulation.
Joint Innervation Overview
A typical joint contains myelinated Aβ, Aδ, and a large number of unmyelinated C fibres. The C fibres are split between sensory afferents and sympathetic afferents. The Aβ fibres are not nociceptive, and have corpuscular endings (Ruffini, Golgi, Pacini) in the fibrous capsule, ligaments, menisci, and periosteum. Aδ and C fibres have free nerve endings that innervate the fibrous capsule, adipose tissue, ligaments, menisci, periosteum, and synovium. The cartilage isn't innervated.
The nerve terminals of the sensory neurons detect and transmit mechanical signals from the joint to the central nervous system. The signals can be low-intensity such as in joint movement leading to the activation of proprioceptors. They can be high-intensity signals as occurs with painful stimuli leading to the activation of nociceptors.
The major neuropeptides are substance P, CGRP, and somatostatin. Neurokinin A, galanin, enkephalins, and neuropeptide Y have also been found.
Typical nerve endings are incompletely covered by Schwann cells. The uncovered areas are thought to be receptive sites along the fibres and appear as a string of beads.
- Characteristics of peripheral nerve fibres
|Nerve Fibre||Myelin||Diameter (µm)||Conduction velocity (m/s)||General Function|
|Aα (I)||Yes||13-20||80-120||Proprioception: muscle spindle primary endings (Ia), golgi tendon organs (Ib), and alpha motor neurons|
|Aβ (II)||Yes||6-12||35-75||Discriminative sensitivity to mechanical stimuli (touch, vibration), proprioception, pain modulation (block nociceptive information, allodynia in sensitisation)|
|Aγ||Yes||4-8||15-40||Touch, pressure, and gamma motor neurons.|
|Aδ (III)||Thin||1-5||5-30||"rapid" pain, crude touch, pressure, temperature. AMH type I for rapid mechanical pain (high heat threshold >53C), AMH type II for rapid heat pain (lower heat threshold 43-47C).|
|C (IV)||No||0.2-1.5||0.5-2.0||"second" pain, mechanical, chemical, thermal, pruritis, and postganglionic autonomic. polymodal|
Joint afferents are able to detect noxious and non-noxious stimuli. Non-noxious stimuli are innocuous loads and movements to the joint. There are four typical joint afferents with differing sensitivities to movement.
Low-threshold Aδ fibres have two receptive fields in the capsule and responds to innocuous stimuli. They are also activated by light pressure. These fibres also respond to noxious stimuli but aren't considered to be principally nociceptive neurons. They rather encode the strength of a stimulus from the non-noxious to noxious range.
There are three other types of fibres, which are a mixture of Aδ and C fibres, and either mainly or exclusively respond to noxious mechanical stimuli (high-threshold). One type are activated only by noxious movements, another are weakly activated by non-noxious movements, and a third are not activated by movements.
A further fibre type are mechano-insensitive and under normal conditions do not respond to either innocuous or noxious stimuli. Some of these become mechanosensitive with inflammation. They are therefore called "silent nociceptors." About one third of the sensory C fibres and small portion of the Aδ fibres are mechano-insensitive, but varies between nerves.
Most Aβ fibres are either strongly or weakly activated by innocuous stimuli. About half of Aδ fibres and about 70% of sensory C fibres are high-threshold units.
The mechano-sensitivity of joint nociceptors is increased with inflammation. Many low-threshold Aδ and C fibres exhibit an increase in response to innocuous stimuli with joint movement in the physiological range. Many high-threshold afferent fibres also become sensitised and respond to innocuous stimuli.
Silent nociceptors become sensitised and become mechanosensitive. They are essentially "awakened" to transmit noxious stimuli during inflammation. This has also been shown to occur in chronic inflammation. This is part of the neuronal process of mechanical allodynia and hyperalgesia.
Most sensory Aδ and C fibres, but not Aβ fibres, are chemo-sensitive and respond to inflammatory mediators. The response to inflammatory mediators is only seen in a subpopulation of the sensory afferents, and different mediators affect different fibres.
The inflammatory mediators include bradykinin, prostaglandin E2 and I2, serotonin, substance P, and VIP. These substances can increase the firing rate of neurons and increase their response to movement leading to sensitisation. The above prostaglandins sensitise the afferents to the effects of bradykinin, and have a greater effect on sensitisation together than either alone. Serotonin also sensitises the sensory afferents.
The peptides galanin, neuropeptide Y, and nociceptin sensitise some neurons and reduce the response of other neurons. Cannabinoids have a mixed effect, they can reduce mechano-sensitivity but activate TRPV1 receptors and cause excitation of sensory afferents. Other mediators have an exclusive inhibitory effect such as opioids, somatostatin.
The proinflammatory cytokines lead to an increase in mechanosensitivity of Aδ and C fibres. These include TNF-alpha, interleukin-1-beta, and interleukin-6.
Hans-Georg Schaible. Articular Nociceptors. Encyclopedia of Pain 2013.