Neural mechanisms underlying the pain of juvenile idiopathic arthritis

Abstract

Pain is the most common symptom of juvenile idiopathic arthritis (JIA) and is arguably a more important factor in disability than the progression of the disease itself. Studies have highlighted the extent of this pain and its persistence in some young patients despite effective disease control. Understanding and effective management of pain in JIA is limited, and improved diagnosis and treatment would benefit from increased knowledge of the mechanisms underlying pain in childhood. This Review focuses upon the developmental neurobiology of pain, reviewing studies in animal models that increase clinical understanding and inform treatment of the painful manifestations of JIA. Pain processing in the juvenile nervous system differs from that in adults: nociceptive thresholds are lower and endogenous pain control systems are slow to mature. Furthermore, increasing evidence points to tissue injury in childhood having prolonged effects upon the developing pain system. Injury, inflammation and stress in early life can 'prime' peripheral nociceptors and central pain circuits, such that the pain associated with tissue inflammation is exacerbated in later life. A developmental, mechanism-based approach towards developing novel targets for the treatment of pain in JIA might therefore benefit the patient both as a child and as an adult if the disease recurs or persists.

Pain hypersensitivity in juvenile idiopathic arthritis: a quantitative sensory testing study

“…Children who underwent cardiac surgery in infancy also exhibit mechanical hyposensitivity in a non-injured thenar eminence site compared to age-matched control [34]. The underlying mechanisms remain unclear but may be due to the fact that different afferent fibers types may be more susceptible to experience-dependent stress, pain exposure, joint damage, and analgesic and anti-inflammatory treatments [3]. …”

“…In addition, central sensitization of sensory circuitry, as characterized by increased neural excitability, strengthened excitatory input and decreased inhibitory activity is thought to be a key component in the transition from acute to chronic pain, and is hypothesized to play a role in pain in adult rheumatologic disease [38]. Finally, descending control from the brainstem, and functional connectivity changes at higher brain centers involved in pain processing at a critical time of synaptic plasticity may be implicated [3]. However, the role of central sensitization in these patients remains speculative, since overall pain reports were low.…”

“…It is characterized by synovial inflammation, resulting in pain, swelling, and stiffness [1, 2]. Pain has a considerable effect on the child’s well-being and is associated with sleep disturbances, functional disability, and psychosocial distress [3]. In some children with JIA whose disease is well-controlled with anti-inflammatory therapy and who have no clinical signs of joint inflammation, pain continues to be a burden [4].…”

“…In some children with JIA whose disease is well-controlled with anti-inflammatory therapy and who have no clinical signs of joint inflammation, pain continues to be a burden [4]. Prolonged pain could be due to ongoing inflammation, or may reflect long-term changes in underlying central and peripheral sensory processing mechanisms during an important time of development in childhood [3]. …”

Long-Term Consequences of Neonatal Injury

“…33 Activity, in terms of sensory influence from the physical environment, provides tactile and noxious input in postnatal life and drives the maturation of high-threshold connectivity and synaptic transmission in the spinal dorsal horn 34 (in addition to endogenous pacemaker activity), which, in turn, drives glycinergic inhibitory maturation. 35 The implications for early pain exposure are 2-fold: first, endogenous spinal inhibitory tone is reduced and less effective, in humans potentially throughout childhood and into early adolescence 36 ; and second, the balance of descending facilitation and inhibition may be disrupted. This is supported by evidence that neonatal hindpaw inflammation leads to long-term alterations in supraspinal circuitry and increased descending inhibition.…”