Physical disuse contributes to widespread chronic mechanical hyperalgesia, tactile allodynia, and cold allodynia through neurogenic inflammation and spino-parabrachio-amygdaloid pathway activation

Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors. The relative proportion of the different fiber types varies strikingly between species, and in humans shows significant variability between individuals. Myosin heavy chain isoforms, whose complete inventory and expression pattern are now available, provide a useful marker for fiber types, both for the four major forms present in trunk and limb muscles and the minor forms present in head and neck muscles. However, muscle fiber diversity involves all functional muscle cell compartments, including membrane excitation, excitation-contraction coupling, contractile machinery, cytoskeleton scaffold, and energy supply systems. Variations within each compartment are limited by the need of matching fiber type properties between different compartments. Nerve activity is a major control mechanism of the fiber type profile, and multiple signaling pathways are implicated in activity-dependent changes of muscle fibers. The characterization of these pathways is raising increasing interest in clinical medicine, given the potentially beneficial effects of muscle fiber type switching in the prevention and treatment of metabolic diseases.

Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.

In an attempt to explain how and why some individuals with musculoskeletal pain develop a chronic pain syndrome, Lethem et al. (Lethem J, Slade PD, Troup JDG, Bentley G. Outline of fear-avoidance model of exaggerated pain perceptions. Behav Res Ther 1983; 21: 401-408).ntroduced a so-called 'fear-avoidance' model. The central concept of their model is fear of pain. 'Confrontation' and 'avoidance' are postulated as the two extreme responses to this fear, of which the former leads to the reduction of fear over time. The latter, however, leads to the maintenance or exacerbation of fear, possibly generating a phobic state. In the last decade, an increasing number of investigations have corroborated and refined the fear-avoidance model. The aim of this paper is to review the existing evidence for the mediating role of pain-related fear, and its immediate and long-term consequences in the initiation and maintenance of chronic pain disability. We first highlight possible precursors of pain-related fear including the role negative appraisal of internal and external stimuli, negative affectivity and anxiety sensitivity may play. Subsequently, a number of fear-related processes will be discussed including escape and avoidance behaviors resulting in poor behavioral performance, hypervigilance to internal and external illness information, muscular reactivity, and physical disuse in terms of deconditioning and guarded movement. We also review the available assessment methods for the quantification of pain-related fear and avoidance. Finally, we discuss the implications of the recent findings for the prevention and treatment of chronic musculoskeletal pain. Although there are still a number of unresolved issues which merit future research attention, pain-related fear and avoidance appear to be an essential feature of the development of a chronic problem for a substantial number of patients with musculoskeletal pain.