Chronic non-inflammatory muscle pain: central and peripheral mediators

Abstract

Conditions with chronic widespread non-inflammatory muscle pain, such as fibromyalgia, have complex etiologies with numerous proposed mechanisms for their pathophysiology of underlying chronic pain. Advancements in neuroimaging have allowed for the study of brain function and connectivity in humans with these conditions, while development of animal models have allowed for the study of both peripheral and central factors that lead to chronic pain. This article reviews the current literature surrounding the pathophysiology of chronic widespread non-inflammatory muscle pain focusing on both peripheral and central nervous system, as well as immune system, contributions to the development and maintenance of pain. A better understanding of the mechanisms underlying these conditions can allow for improvements in patient education, treatment and outcomes.

Keywords: Chronic pain; central sensitization; hyperalgesia; muscle pain; neurobiology.

Figure 1.

(A) Illustration of hyperalgesic priming. A single priming stimulus produces a short-lived hyperalgesic response that resolves (green). A second inducing stimulus, given within a critical window, will then produce a longer-lasting and more robust hyperalgesia (orange). For comparison the initial priming response is overlayed on the enhanced response. Copyright by Dr. Kathleen Sluka. (B) Intraomuscular injection of pH 4.0 produces a short duration decrease in withdrawal threshold to mechanical stimulation of the paw. A second injection 5 days later produces a greater and longer lasting decrease in withdrawal threshold. Reproduced with permission from(5). (C) Injection of NGF into human masseter (MA) muscle caused a decrease in masseter muscle pressure pain thresholds (PPT) at day 1 and day 7 following injection. This effect was localized to the masseter muscle since no decrease in PPT at the masseter muscle was seen following injection of NGF into the temporalis (TA) muscle. Muscle contraction produces pain over the tibialis anterior muscle after NGF injection that results in a greater area of pain after several days. Reproduced with permission from(33, 34). (D) Model of peripheral mediators implicated in the development of pain. Fatigue metabolites (H+, ATP) and nerve growth factor (NGF) secreted from muscles activate nociceptors by binding to their receptors. Fatigue metabolites also activate macrophages to increase the production of inflammatory cytokines which work to activate nociceptors. Copyright by Dr. Kathleen Sluka.

Figure 2.

(A) Higher degree of intrinsic connectivity is seen between the default mode network (DMN) and the insula in people with fibromyalgia (FM). Intrinsic DMN connectivity to the right (R) anterior and middle insula was correlated greater spontaneous pain intensity on a visual analog scale (VAS) at the time of the fMRI. Red circles represent individuals with FM. Reproduced with permission(73). (B) Increased activity in the anterior and posterior middle cingulate cortex (MCC) measured by standardized uptake value ratio (SUVR) was found for individuals with FM reporting higher levels of fatigue on the American College of Rheumatology (ACR) fibromyalgia diagnostic criteria. There were no other significant associations between SUVR at these cortical sites and any other clinical variable. Reproduced with permission from(83). (C) Blockade of the serotonin transporter by 20 nmol of fluoxetine injected in the rostral ventromedial medulla (RVM) 24 hours after the second acid injection resulted in a reversal of hyperalgesia measured by muscle withdrawal thresholds in the acid hyperalgesic priming model. Reproduced from(103). Immunohistochemical staining of SERT in the nucleus raphe obscurus (NRO), nucleus raphe pallidus (NRP) and nucleus raphe magnus (NRM) in naïve and WT mice 24 hours after induction of activity-induced hyperalgesia priming model. There was an increase in the SERT immunoreactivity in the NRO, NRM and NRP of the RVM in WT mice following induction of the model. Reproduced with permission from(104). (D) Blockade of ERK with the MEK inhibitor during the priming injection prevented development of hyperalgesia after the second injection. Photomicrographs show immunohistochemical staining for phosphorylated extracellular signal-related kinases (pERK) in the dorsal horn of the spinal cord 2 hours after the acid priming injection. The bar graphs show a significant increase in the number of cells labeled with p-ERK after the first priming injection compared to pH 7.2 injection. Reproduced with permission from(107).