Chronic Pain: Alterations of Functional Structures

The goal of this review is to provide a comprehensive overview of the alterations that occur in the transition from acute to chronic pain states in peripheral and central nervous structures. Chronic or persistent pain is a devastating condition for affected individuals and to the society loaded with immense costs, as it is often difficult or impossible to treat. Unlike acute pain, chronic pain is maladaptive and is usually associated with severe changes in brain structures and functions, potentially including psychiatric diseases like anxiety and depressive disorders. Unfortunately, and for still ill-known reasons, certain acute pain states tend to become chronic. As will turn out throughout this review, chronic pain and the underlying neuronal systems are highly complex. There are many reasons for this complexity, exhibiting several layers, the first sub-cellular layer not even being touched upon here. The next higher level consists of a multiplicity of involved macroscopic structures: nociceptors, various nuclei, cortices etc., which have themselves complicated internal structures with diverse cell types of different morphologies, functions and internal non-linear interactions. Third, individual neuronal nodes usually receive multiple intputs from, and send multiple outputs to, other nodes, thus creating an extended macroscopic network. Fourth, the operation of this network is modulated and changed by many diverse neuromodulators, many of which in addition work on more than one receptors. Fifth, multiple parallel effects may be exerted on anyone structure, for example, the spinal dorsal horn (DH). In brief, the pain-processing networks are multi-functional, fluid and dependent on many external influences, reflecting a general principle or “Bauplan” of the nervous system. This review adds yet another layer: the impact of multifarious diseases that disturb the workings of the networks under `normal´ conditions and promote maladaptive plasticity. It is difficult to envision the interactions between the multitudes of time- and condition-dependent factors and influences. After a characterization of chronic pain, the discussion will follow a path from the periphery to the uppermost central structures that is from the nociceptors to the cerebral cortex, integrating peripheral sensitization, central sensitization, neuroinflammatory processes, and large-scale brain reorganization