Pathophysiology of musculoskeletal pain: a narrative review

Abstract

Musculoskeletal pain (excluding bone cancer pain) affects more than 30% of the global population and imposes an enormous burden on patients, families, and caregivers related to functional limitation, emotional distress, effects on mood, loss of independence, and reduced quality of life. The pathogenic mechanisms of musculoskeletal pain relate to the differential sensory innervation of bones, joints, and muscles as opposed to skin and involve a number of peripheral and central nervous system cells and mediators. The interplay of neurons and non-neural cells (e.g. glial, mesenchymal, and immune cells) amplifies and sensitizes pain signals in a manner that leads to cortical remodeling. Moreover, sex, age, mood, and social factors, together with beliefs, thoughts, and pain behaviors influence the way in which musculoskeletal pain manifests and is understood and assessed. The aim of this narrative review is to summarize the different pathogenic mechanisms underlying musculoskeletal pain and how these mechanisms interact to promote the transition from acute to chronic pain.

Keywords: arthralgia; musculoskeletal pain; myalgia; neuroglia; physiology.

Figure 1.

Organization of bone innervation of the periosteum, cortical bone, and marrow. On the left side, main stimuli and mediators of bone pain are shown. Green dotted lines represent Aδ fibers, purple lines C-fibers, and yellow lines sympathetic fibers. Numbers shown refer to the relative density of nervous fibers in the periosteum, cortical bone, and marrow, respectively. See text for details. ATP, adenosine triphosphate; ILs, interleukins; NGF, nerve growth factor; PGE2, prostaglandin E2.

Figure 2.

Joint and muscle innervation. Aδ fibers (green dotted lines) innervate ligaments while intraarticular structures are mostly innervated by C-sensory (violet lines) and sympathetic fibers (yellow lines). Cartilage (in light blue) is aneural and avascular under physiologic conditions.

Figure 3.

Schematic representation of the contribution of mast cells and microglia to degenerative joint diseases and neuro-inflammation. At the articular level, mast cells are located mainly in the synovial membrane and joint capsule, and elsewhere, mostly along blood vessels and nerve endings of the joint. Peripheral and central mast cells are likely play a crucial role in the shift of acute to chronic pain by interacting with other immune cells and somatosensory nerve terminals. In the periphery, persistent mast-cell activation promotes the recruitment of other immune cells such as lymphocytes at the lesion site, amplifying inflammatory processes and causing a sensitization of peripheral nociceptors and spinal somatosensory neurons. In the CNS, mast cells amplify neuro-inflammatory processes by promoting glial-cell activation, which coordinates inflammation at the spinal level and central sensitization of central somatosensory neurons (courtesy of Wiley). CNS, central nervous system.

Figure 4.

Resting and primed microglia: the main differences. With aging and/or pain stimulus, the phenotype of microglia becomes predominantly primed. It responds in a more intense manner, producing a greater amount of pro-inflammatory mediators and for a longer time. Primed microglia induce persistent neuro-inflammatory response, capable of damaging tissue integrity and neuron function. (Courtesy of the Paolo Procacci Foundation.)