Conceptual basis of pain medicine: Basic sciences

Abstract
Pain is both a sensory event of the peripheral and central nervous systems and an experience that arises from, and reciprocally can affect processes of higher consciousness. Alterations in peripheral and central neuraxes can lead to sensitization, structural modification and long-term potentiation that can overcome modulatory influence(s) and change the non-linear adaptability of these systems to a progressively linear, pathologic state with a diverse constellation of clinical signs and symptoms. Recent progress in molecular biology, neurochemistry and neuroanatomy has led to significant advancement in understanding the interactive roles of these heterogeneous systems in mediating and modulating various types of pain. This review concisely provides an overview of the structure and function of these substrates. As we reach the midpoint in a decade marked by pain control and research, such knowledge is critical to further both a more comprehensive appreciation of the phenomenon that is pain, and the development of therapeutic interventions that are innovative and effective.

Abstract
Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.