Musculoskeletal Pain Kathryn Albers Mechanisms and Clinical Presentation of Pain November 4, 2019 Queme et al., (2017). Peripheral mechanisms of ischemic myalgia. Frontiers in Cellular Neuroscience. Mense et al., (2010). Functional anatomy of muscle: Muscle, nociceptors and afferent fibers. In MusclePain: Understanding the Mechanisms. The musculoskeletal system consists of the body's bones, muscles, tendons, ligaments, joints, and cartilage. A tendon is a fibrous connective tissue that attaches muscle to bone (serves to move the bone). A ligament is a fibrous connective tissue that attaches bone to bone (serves to hold structures together). Major health problems presenting with muscle ache/pain are addressed by NIAMS, National Institutes of Arthritis, Musculoskeletal and Skin Diseases. Neck pain Temperomandibular joint pain Fibromyalgia Shoulder pain Low back pain Skeletal muscle comprises 40% of body weight. Muscles produce several hundred myokines; cytokines, growth factors, proteoglycan peptides released by muscle cells (myocytes) in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects on muscle mass, fat metabolism, inflammation…. Lee and Jun. (2019) Role of myokines in regulating skeletal muscle mass and function. Frontiers in Physiology 10. Musculoskeletal Pain Overview Physical activity leads to contraction-induced mechanical and metabolic stimuli in muscle tissue. These stimuli activate receptors on terminals of thinly myelinated and unmyelinated DRG neurons that project to the DH of the spinal cord. • Chronic muscle pain can be regional (back or neck) or whole body with tender points spread over the body (fibromyalgia). • In contrast to cutaneous nociceptive stimuli, sensations from deep tissue (muscle, vascular, fascia) pain are dull, aching and poorly localized. Muscle pain can also elicit a drop in blood pressure, sweating and nausea. • Pain can relate to dysfunction of peripheral perfusion (e.g., peripheral vascular disease) and are often comorbid with altered cardiovascular responses to muscle contraction/exercise (exercise pressor reflex, EPR). Musculoskeletal Pain Overview, continued • Muscle pain (myalgia) can present as • Inflammatory, e.g., rheumatoid arthritis (autoimmune, widespread), exercise-induced • Degenerative/inflammatory – osteoarthritis (localized to joints) • Possibly inflammatory – • fibromyalgia, • low back pain • myofascial (muscle-connective tissue) pain syndrome, where pressure on sensitive points in the muscle (knots) is painful. MPS typically caused by repetitive motions or stress-related muscle tension. Cellular basis of muscle pain: 1. Myositis – general term for inflammation of the muscle. - Injury, infection or autoimmune disease can cause polymyositis. Immune activation generates interleukins, TNF, chemokines, growth factors. 2. Tissue acidosis, a decrease in local tissue pH. - Pain correlates with increased protons (H+) and lactate buildup in muscle/synovial fluid - Infusion of acidic solutions (pH 5.2) into muscle causes mechanical hyperalgesia in human and in rodent models. 3. Dysregulation of metabolite levels - ATP, lactate and protons. Infusion of metabolite soup into muscle is painful. 10 volunteers (6 men/4 women) 0.2ml protons/ATP/lactate infused over 30s under fascia of thumb muscle. Exp Physiol 99.2(2014)368. Findings: • Low conc of protons, lactate and ATP evoked sensations related to fatigue. • Higher conc evoked pain. • Single metabolites evoked no sensations • Interpretations: - Two types of sensory neurons encode metabolites; one detects low concentrations, signals fatigue. The other detects higher conc and signals ‘ache and hot’. - In human, metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain. Do metabolites enhance sensitivity of muscle afferents in chronic disease states, e.g., fibromyalgia? Muscle Morphology Straited (skeletal) – voluntary, ~40% of body weight Cardiac - involuntary Smooth - involuntary connective tissue connective tissue connective tissue Fig. 2.1 From S. Mense et al., Functional Anatomy of Muscle: Muscle, Muscle Nociceptors and Afferent Fibers. S. Mense and R.D. Gerwin (eds.), Muscle Pain: Understanding the Mechanisms, DOI 10.1007/978-3-540-85021-2_2, # Springer-Verlag Berlin Heidelberg 2010 Muscle Innervation e.g., knee Group I-IV nomenclature introduced by DPC Lloyd, 1943. Afferent fiber types • Group Ia, II – assoc with muscle spindles; respond to stretch, changes in muscle length. • Group III – thinly myelinated A delta fibers • Group IV - unmyelinated C fibers Group III/IV afferents primarily project to sc lamina I, II (less so to IV-V). Efferent motor neurons: Alpha – innervate extrafusal fibers and intiate muscle contraction. Gamma – innervate intrafusal muscle fibers in the muscle spindle. Beta motor neurons – innervate both extra- and intra –fusal fibers. Very few of these. Properties of Muscle Nociceptors • Relatively slow conducting, below 20-30 m/s (species dependent) (fastest fibers reach 100 m/s). • Thin myelinated, group III fibers – correspond in conduction velocity to cutaneous Ad fibers. 1.2 - 14 m/s (in mouse) • Unmyelinated group IV fibers – correspond in conduction velocity to cutaneous C fibers. <1.2 m/s (mouse) a-CGRP • Group III and group IV fibers function as chemo-, thermo- and mechano-receptors, functional overlap unclear *. arteriole • Many Group III/IV fibers innervate adventitia of vasculature and perimysium; few innervate muscle fibers**. *Light AR, Perl ER (2003) Unmyelinated afferent fibers are not only for pain anymore. J Comp Neurol 461:140–150. Discusses muscle LTMRs. **Reinert A, Kaske A, Mense S (1998) Inflammation-induced increase in the density of neuropeptide-immunoreactive nerve endings in rat skeletal muscle. Exp Brain Res 121:174–180 Fig. 2.5 From Mense et al., Muscle Pain: Understanding the Mechanisms, DOI 10.1007/978- 3-540-85021-2_2, 2010 That muscle fibers themselves are not supplied by free nerve endings may relate to the clinical experience that muscle cell death is usually not painful, at least not if it occurs slowly, as during muscular dystrophy, polymyositis, or dermatomyositis (skin rash with muscle inflammation). A different situation is tearing of a muscle fiber bundle, which can be extremely painful. Many muscle cells are destroyed simultaneously and release their contents (e.g., K+ ions, ATP) in the interstitial space, from where they can diffuse to nociceptive endings. S. Mense Review: Functional Anatomy of Muscle: Muscle, Nociceptors and Afferent Fibers Membrane receptors associated with nociception are expressed by muscle afferents. Most studied are: Acid Sensing Ion Channels - sensitive to H+; activated by change in pH produced by exercise, ischemia, inflammation. TRPV1 – sensitive to H+, lipids (anadamide), heat P2X3/5 – activated by ATP Evidence suggests interaction of receptor types on skeletal muscle afferent endings, e.g., P2X/ASICs Birdsong et al (2010) Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels. Neuron 68:739. Models of Muscle Pain • Injection/continuous infusion of algogenic compounds: (carrageenan, mustard oil, immune modulators). • Acid model – Injection(s) of acidic saline causes mech allodynia via activation of acid sensing ion channels (ASICs). - Non-inflammatory - Inhibition of acid pain by opioids, NMDA blockers, pregabalin and exercise but not to NSAIDs. • Exercise induced: delayed onset of muscle soreness model. Produces micro tears that cause pain and increased lactate, glutamate, PGE2, SubP. • Exercise (wheel running) plus acid, e.g., pH 5 • Injection of metabolites produced by muscle contraction - combination of ATP, lactate, protons (H+) act synergistically to activate receptors. • Prolonged ischemia (e.g., 6h surgical occlusion, brachial artery) – models pain associated with conditions that can produce ischemia/reperfusion injuries: complex regional pain syndrome (CRPS), peripheral vascular disease (PVD), sickle cell anemia and fibromyalgia. • Clinical features of ischemic myalgia include decreased activity, ongoing pain, hypersensitivity, and weakness in the affected muscle tissue. In contrast to nociceptive stimuli from skin, muscle activity/pain can elicit a cardiovascular (exercise pressor) reflex, i.e., increased heart rate, blood pressure, sweating. Activation of Group III/IV afferents - transmit muscle pain and affect autonomic (sympathetic) responses. • Ablation/anesthetic block of group III/IV neurons abolishes the EPR in response to muscle contraction. • Patients with CRPS or vascular disease have exaggerated EPRs. • Both pain and change in cardiovascular reflexes in response to ischemic damage involves upregulation of P2Y1 in primary afferents. Queme, Ross and Jankowski. 2017. Peripheral mechanisms of ischemic myalgia. ischemic of 2017.mechanisms Peripheral Jankowski.and RossQueme, Neuroscience. in Cellular Frontiers Acid activates Acid Sensing Ion Channels (ASICs), a subfamily of the epithelial sodium channel (ENaC/degenerin) ion channel superfamily Voltage independent, proton-gated sodium channels that detect change in pH (5-8; tissue acidification) under pathological and non- pathological conditions: ischemia, fatiguing muscle exercise, cancer, neuronal activity, inflammation. ASICs1-5 genes have splice variants and protein isoforms. Most common ASIC1a, ASIC1a/2a, ASIC3. Studies support major role for ASIC3 in nociception: Injection of acid causes pain; pain is absent