Autoantibodies Produce Pain in Complex Regional Pain Syndrome by Sensitizing Nociceptors

Ulku Cuhadar; Clive Gentry; Nisha Vastani; Serena Sensi; Stuart Bevan; Andreas Goebel; David A. Andersson


Pain. 2019;160(12):2855-2865. 

In This Article

Abstract and Introduction


Complex regional pain syndrome (CRPS) is a posttraumatic pain condition with an incompletely understood pathophysiological basis. Here, we have examined the cellular basis of pain in CRPS using behavioral and electrophysiological methods in mice treated with IgG from CRPS patients, in combination with a paw incision. Mice were subjected to a hind paw skin–muscle incision alone, or in combination with administration of IgG purified from either healthy control subjects or patients with persistent CRPS. Nociceptive function was examined behaviorally in vivo, and electrophysiologically in vitro using skin–nerve preparations to study the major classes of mechanosensitive single units. Administration of IgG from CRPS patients exacerbated and prolonged the postsurgical hypersensitivity to noxious mechanical, cold, and heat stimulation, but did not influence tactile sensitivity after a paw incision. Studies of IgG preparations pooled from patient cohorts (n = 26–27) show that pathological autoantibodies are present in the wider population of patients with persistent CRPS, and that patients with more severe pain have higher effective autoantibody titres than patients with moderate pain intensity. Electrophysiological investigation of skin–nerve preparations from mice treated with CRPS IgG from a single patient identified both a significantly increased evoked impulse activity in A and C nociceptors, and an increased spontaneous impulse rate in the intact saphenous nerve. Our results show that painful hypersensitivity in persistent CRPS is maintained by autoantibodies, which act by sensitizing A and C nociceptors.


Complex regional pain syndrome (CRPS) is a posttraumatic condition typically confined to a single limb. Complex regional pain syndrome is characterized by pain of disproportionate intensity and duration compared with that expected from the clinical time course of the initial injury or trauma, but the etiology and pathophysiological basis of CRPS are incompletely understood.[6,22,37,39,53] Distal limb fractures are the most common triggers of CRPS, but the severity of CRPS is independent of the initiating trauma, and apparently trivial insults can lead to CRPS.[43,61] The affected limb typically exhibits several characteristic abnormalities, including increased sensitivity to both normally innocuous and painful stimuli, skin discoloration, fluctuating temperature asymmetry (compared with the uninjured limb), swelling, sudomotor alterations, and trophic changes to skin, hair, and nails. Pain is, however, the dominant symptom and CRPS is not associated with tissue destruction.[9,53] No diagnostic tests exist for CRPS, and patients are diagnosed based on clinical symptoms and signs.[10,23,30] Most patients recover spontaneously, but 15% to 20% of patients develop persistent severe pain, which may last for life and is associated with an exceptionally low quality of life, even when compared to other chronic pain conditions.[40,59] The characteristic autonomic abnormalities seen early in the course of CRPS typically normalize in patients with long-standing disease, whereas pain as well as sensory and motor abnormalities may remain. This has led to suggestions that persistent CRPS is sustained by abnormal central nervous system plasticity.[46]

Earlier investigations have demonstrated that administration of IgG from patients with persistent CRPS (>1 year duration) to mice reduced spontaneous rearing in freely moving mice.[28] When IgG transfer was combined with a paw incision as an experimental insult, a transiently enhanced postsurgical swelling and mechanical hypersensitivity in the injured paw were observed.[27] Later studies demonstrated that immunoglobulins of other isotypes were inactive because transfer of IgG-depleted serum was without effect.[55] These results indicate that IgG autoantibodies are central for the genesis and maintenance of pain and painful hypersensitivities in persistent CRPS. Importantly, the underlying neuronal mechanisms and sites of action responsible for pain have not been identified.

In this study, we have performed a detailed behavioral and electrophysiological investigation of painful sensory abnormalities in the passive transfer-trauma model of CRPS (tCRPS[55]) and identified peripheral sensitization of nociceptors as a major mechanism by which autoantibodies produce pain in CRPS.