Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

Abstract

Pain due to osteoarthritis (OA) is one of the most frequent causes of chronic pain. However, the mechanisms of OA pain are poorly understood. This review addresses the mechanisms which are thought to be involved in OA pain, derived from studies on pain mechanisms in humans and in experimental models of OA. Three areas will be considered, namely local processes in the joint associated with OA pain, neuronal mechanisms involved in OA pain, and general factors which influence OA pain. Except the cartilage all structures of the joints are innervated by nociceptors. Although the hallmark of OA is the degradation of the cartilage, OA joints show multiple structural alterations of cartilage, bone and synovial tissue. In particular synovitis and bone marrow lesions have been proposed to determine OA pain whereas the contribution of the other pathologies to pain generation has been studied less. Concerning the peripheral neuronal mechanisms of OA pain, peripheral nociceptive sensitization was shown, and neuropathic mechanisms may be involved at some stages. Structural changes of joint innervation such as local loss and/or sprouting of nerve fibers were shown. In addition, central sensitization, reduction of descending inhibition, descending excitation and cortical atrophies were observed in OA. The combination of different neuronal mechanisms may define the particular pain phenotype in an OA patient. Among mediators involved in OA pain, nerve growth factor (NGF) is in the focus because antibodies against NGF significantly reduce OA pain. Several studies show that neutralization of interleukin-1β and TNF may reduce OA pain. Many patients with OA exhibit comorbidities such as obesity, low grade systemic inflammation and diabetes mellitus. These comorbidities can significantly influence the course of OA, and pain research just began to study the significance of such factors in pain generation. In addition, psychologic and socioeconomic factors may aggravate OA pain, and in some cases genetic factors influencing OA pain were found. Considering the local factors in the joint, the neuronal processes and the comorbidities, a better definition of OA pain phenotypes may become possible. Studies are under way in order to improve OA and OA pain monitoring.

Spontaneous dog osteoarthritis — a One Medicine vision

“…Similarities in neurophysiology across mammals strongly suggest that the type of pain experienced by humans and animals is analogous 210 . However, pain experiences in OA are complicated and involve peripheral nociceptive sensitization, structural changes to joint innervation, central nervous system sensitization, neuropathic changes and a host of mediators, as well as simple nociceptive input from damaged joint tissues 212 . Pain severity correlates poorly with radiographic structural changes in humans 213 and dogs 214 with OA.…”

“…The development of new therapies for pain in OA will therefore require effective models that recapitulate the joint changes that occur in OA, as well as the clinical symptoms. Levels of pain in OA are affected by synovitis, osteochondral pathology and sensitization, which are not accounted for by structural radiographic changes 212,215 . Good models of OA therefore need to reflect the longitudinal natural history of human OA phenotypes 216,217 .…”

Understanding the pain profile in patients with haemophilia: Impaired descending pain inhibition as measured by conditioned pain modulation

“…A recent review describes the pain mechanisms in osteoarthritis and points out that endogenous descending pain inhibition is also impaired in the presence of severe osteoarthritis. The authors of this review reasonably postulate that the severity of pain in osteoarthritic patients is partly caused by a ‘distortion of the balance between [the] inhibitory and excitatory modulation descending systems’ . Important key players are serotonin and norepinephrine which regulate the pain processing and modulate the signals coming from the brain down to the spinal cord .…”

Mechanisms Underlying Bone and Joint Pain

“…twisted joint, stressful impact) or from actual damaged tissue activate specialized sensory neurons known as nociceptors. Both bone and joint tissue are innervated by these specialized neurons which allow for the transduction of painful stimuli to aid in preventing further damage to tissue and repeating potentially tissue damaging behaviors [5–8]. Multiple classes of nociceptors have been studied to date, differentiated by their cell body and axon size, their myelination patterns and electrophysiological characteristics such as conduction velocity and response thresholds, and the characteristics of stimuli that they respond to [9–12].…”

“…Many animal and clinical studies have demonstrated that sensitization of peripheral and central neurons develops in the context of chronic bone or joint pain [5, 67, 78]. The international association for the study of pain (IASP) defines sensitization as “Increased responsiveness of nociceptive neurons to their normal input, and/or recruitment of a response to normally subthreshold inputs”.…”