Neurobiology of fibromyalgia and chronic widespread pain.

Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excit...

Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors

Background Exercise is an effective treatment for various chronic pain disorders, including fibromyalgia, chronic neck pain, osteoarthritis, rheumatoid arthritis, and chronic low back pain. Although the clinical benefits of exercise therapy in these populations are well established (i.e. evidence based), it is currently unclear whether exercise has positive effects on the processes involved in chronic pain (e.g. central pain modulation). Objectives Reviewing the available evidence addressing the effects of exercise on central pain modulation in patients with chronic pain. Methods Narrative review. Results Exercise activates endogenous analgesia in healthy individuals. The increased pain threshold following exercise is due to the release of endogenous opioids and activation of (supra)spinal nociceptive inhibitory mechanisms orchestrated by the brain. Exercise triggers the release of beta-endorphins from the pituitary (peripherally) and the hypothalamus (centrally), which in turn enables analgesic effects by activating μ-opioid receptors peripherally and centrally, respectively. The hypothalamus, through its projections on the periaqueductal grey, has the capacity to activate descending nociceptive inhibitory mechanisms. However, several groups have shown dysfunctioning of endogenous analgesia in response to exercise in patients with chronic pain. Muscle contractions activate generalized endogenous analgesia in healthy, pain-free humans and patients with either osteoarthritis or rheumatoid arthritis, but result in increased generalised pain sensitivity in fibromyalgia patients. In patients having local muscular pain (e.g. shoulder myalgia), exercising non-painful muscles activates generalized endogenous analgesia. However, exercising painful muscles does not change pain sensitivity either in the exercising muscle or at distant locations. Limitations The reviewed studies examined acute effects of exercise rather than long-term effects of exercise therapy. Conclusions A dysfunctional response of patients with chronic pain and aberrations in central pain modulation to exercise has been shown, indicating that exercise therapy should be individually tailored with emphasis on prevention of symptom flares. The paper discusses the translation of these findings to rehabilitation practice together with future research avenues.

https://biblio.ugent.be/publication/2964153/file/2964154.pdf

Dysfunctional Endogenous Analgesia During Exercise in Patients with Chronic Pain: To Exercise or Not to Exercise?

The response of skeletal muscle to unaccustomed eccentric exercise has been studied widely, yet it is incompletely understood. This review is intended to provide an up-to-date overview of our understanding of how skeletal muscle responds to eccentric actions, with particular emphasis on the underlying molecular and cellular mechanisms of damage and recovery. This review begins by addressing the question of whether eccentric actions result in physical damage to muscle fibers and/or connective tissue. We next review the symptomatic manifestations of eccentric exercise (i.e., indirect damage markers, such as delayed onset muscle soreness), with emphasis on their relatively poorly understood molecular underpinnings. We then highlight factors that potentially modify the muscle damage response following eccentric exercise. Finally, we explore the utility of using eccentric training to improve muscle function in populations of healthy and aging individuals, as well as those living with neuromuscular disorders.

Lengthening our perspective: morphological, cellular, and molecular responses to eccentric exercise.

The purpose of this study was to test the hypothesis that remodeling of skeletal muscle extracellular matrix (ECM) is involved in protecting human muscle against injury. Biopsies were obtained from medial gastrocnemius muscles after a single bout of electrical stimulation (B) or a repeated bout (RB) 30 d later, or 30 d after a single stimulation bout (RBc). A muscle biopsy was collected from the control leg for comparison with the stimulated leg. Satellite cell content, tenascin C, and muscle regeneration were assessed by immunohistochemistry; real-time PCR was used to measure mRNA levels of collagens, laminins, heat-shock proteins (HSPs), inflammation, and related growth factors. The large responses of HSPs, CCL2, and tenascin C detected 48 h after a single bout were attenuated in the RB trial, indicative of protection against injury. Satellite cell content and 12 target genes, including IGF-1, were elevated 30 d after a single bout. Among those displaying the greatest difference vs. control muscle, ECM laminin-β1 and collagen types I and III were elevated ∼6- to 9-fold (P<0.001). The findings indicate that the sequenced events of load-induced early deadhesion and later strengthening of skeletal muscle ECM play a role in protecting human muscle against future injury.

Sequenced response of extracellular matrix deadhesion and fibrotic regulators after muscle damage is involved in protection against future injury in human skeletal muscle

Unaccustomed strenuous exercise that includes lengthening contraction (LC) often causes delayed-onset muscle soreness (DOMS), a kind of muscular mechanical hyperalgesia. The substances that induce this phenomenon are largely unknown. Peculiarly, DOMS is not perceived during and shortly after exercise, but rather is first perceived after ∼1 d. Using B2 bradykinin receptor antagonist HOE 140, we show here that bradykinin released during exercise plays a pivotal role in triggering the process that leads to muscular mechanical hyperalgesia. HOE 140 completely suppressed the development of muscular mechanical hyperalgesia when injected before LC, but when injected 2 d after LC failed to reverse mechanical hyperalgesia that had already developed. B1 antagonist was ineffective, regardless of the timing of its injection. Upregulation of nerve growth factor (NGF) mRNA and protein occurred in exercised muscle over a comparable time course (12 h to 2 d after LC) for muscle mechanical hyperalgesia. Antibodies to NGF injected intramuscularly 2 d after exercise reversed muscle mechanical hyperalgesia. HOE 140 inhibited the upregulation of NGF. In contrast, shortening contraction or stretching induced neither mechanical hyperalgesia nor NGF upregulation. Bradykinin together with shortening contraction, but not bradykinin alone, reproduced lasting mechanical hyperalgesia. We also showed that rat NGF sensitized thin-fiber afferents to mechanical stimulation in the periphery after 10–20 min. Thus, NGF upregulation through activation of B2 bradykinin receptors is essential (though not satisfactory) to mechanical hyperalgesia after exercise. The present observations explain why DOMS occurs with a delay, and why lengthening contraction but not shortening contraction induces DOMS.

https://www.jneurosci.org/content/jneuro/30/10/3752.full.pdf

Hisako Urai

Papers

Bradykinin and Nerve Growth Factor Play Pivotal Roles in Muscular Mechanical Hyperalgesia after Exercise (Delayed-Onset Muscle Soreness)