Chronic Pain after Bone Fracture: Current Insights into Molecular Mechanisms and Therapeutic Strategies.

Bone fracture following traumatic injury or due to osteoporosis is characterized by severe pain and motor impairment and is a major cause of global mortality and disability. Fracture pain often originates from mechanical distortion of somatosensory nerve terminals innervating bones and muscles and is maintained by central sensitization. Chronic fracture pain (CFP) after orthopedic repairs is considered one of the most critical contributors to interference with the physical rehabilitation and musculoskeletal functional recovery. Analgesics available for CFP in clinics not only have poor curative potency but also have considerable side effects; therefore, it is important to further explore the pathogenesis of CFP and identify safe and effective therapies. The typical physiopathological characteristics of CFP are a neuroinflammatory response and excitatory synaptic plasticity, but the specific molecular mechanisms involved remain poorly elucidated. Recent progress has deepened our understanding of the emerging properties of chemokine production, proinflammatory mediator secretion, caspase activation, neurotransmitter release, and neuron-glia interaction in initiating and sustaining synaptogenesis, synaptic strength, and signal transduction in central pain sensitization, indicating the possibility of targeting neuroinflammation to prevent and treat CFP. This review summarizes current literature on the excitatory synaptic plasticity, microgliosis, and microglial activation-associated signaling molecules and discusses the unconventional modulation of caspases and stimulator of interferon genes (STING) in the pathophysiology of CFP. We also review the mechanisms of action of analgesics in the clinic and their side effects as well as promising therapeutic candidates (e.g., specialized pro-resolving mediators, a caspase-6 inhibitor, and a STING agonist) for pain relief by the attenuation of neuroinflammation with the aim of better managing patients undergoing CFP in the clinical setting.