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Abstract

Arthritis pain affects millions of people worldwide yet we still have only a limited understanding of what makes our joints ache. This review examines the sensory innervation of diarthroidal joints and discusses the neurophysiological processes that lead to the generation of painful sensation. During inflammation, joint nerves become sensitized to mechanical stimuli through the actions of neuropeptides, eicosanoids, proteinase-activated receptors and ion channel ligands. The contribution of immunocytes to arthritis pain is also reviewed. Finally, the existence of an endogenous analgesic system in joints is considered and the reasons for its inability to control pain are postulated. IntroductionAccording to a recent report released by the World Health Organization [1], musculoskeletal disorders are the most frequent cause of disability in the modern world, and the prevalence of these diseases is rising at an alarming rate. The most prominent reason for loss of joint mobility and function is chronic or episodic pain, which leads to psychological distress and impaired quality of life. Current therapies to help alleviate joint pain have limited effectiveness and certain drugs produce unwanted negative side effects, thereby precluding their long-term use. In short, millions of patients are suffering from the debilitating effects of joint pain for which there is no satisfactory treatment. One of the reasons for this lack of effective pain management is the paucity in our knowledge of what actually causes joint pain. We are only now starting to identify some of the mediators and mechanisms that cause joints to become painful, allowing us to develop future new targets that could better alleviate arthritis pain. This review summarizes what is known about the origin of joint pain by describing the neurobiological processes initiated in the joint that give rise to neural signals and that are ultimately decoded by the central nervous system into pain perception. Joint innervation and nociceptionKnee joints are richly innervated by sensory and sympathetic nerves [2,3]. Postganglionic sympathetic fibres terminate near articular blood vessels, where they regulate joint blood flow through varying degrees of vasoconstrictor tone. The primary function of sensory nerves is to detect and transmit mechanical information from the joint to the central nervous system. Large diameter myelinated nerve fibres encode and transmit proprioceptive signals, which can be interpreted as being either dynamic (movement sensations) or static (position sense). Pain-sensing nerve fibres are typically less than 5 µm in diameter and are either unmyelinated (type IV) or myelinated with an unmyelinated 'free' nerve ending (type III). These slowly conducting fibres typically have a high threshold and only respond to noxious mechanical stimuli, and as such are referred to as nociceptors [4]. In the rat and cat, 80% of all knee joint afferent nerve fibres are nociceptive [5][6][7], suggesting that joints are astutely designed to sense abnormal and p...

PKCδnull mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth

“…34 Angiogenic features in experimental OA resemble those pathological changes seen in OA patients with chronic joint pain. [19][20][21] We found significantly increased angiogenic activity in PKCδ null mice (compared with WT mice) during OA progression.…”

Towards a mechanism-based approach to pain management in osteoarthritis

“…In rats and cats, reportedly 80% of all afferent neurons in the knee joint are nociceptors. 24 In humans, articular branches of the tibial nerve that innervate the posterior knee joint capsule contain 70–80% unmyelinated C-fibres and sympathetic nerves (which have also been associated with pain). 25 Nociceptors are abundant in the joint capsule, ligaments, periosteum, menisci, subchondral bone and synovium.…”

New advances in musculoskeletal pain

“…This secondary mechanical allodynia, or referred pain, develops in the MIA model as well and can be reversed with compounds and drugs designed to target neuropathic pain, such as opiates and gabapentin, providing further support for the utility of the MIA model for testing of compounds for therapeutic intervention in OA (Combe et al, 2004; Fernihough et al, 2004; Beyreuther et al, 2007). In addition to pharmacological characterization of this model, a host of investigators have started to utilize other technologies to further assess the potential translatability of this model to the clinic, including image analysis using MRI, µCT and ultrasound, electrophysiology studies, and gait analysis (Morenko et al, 2004; Schuelert and McDougall, 2006, 2008). …”

“…Though progress has been made, little is understood in how pain occurs in OA, and its similarities and differences to other pain states, such as inflammatory and neuropathic pain. Future challenges will include identifying the site of the pain in the OA joint, as there is a poor correlation between histological and radiological joint damage and pain (McDougall, 2006). The use of animal models will be vital for the investigation of changes in disease as clinical samples of these areas are unavailable.…”