Figure 1: Hypothesized signaling pathways of myofascial trigger points and therapies. A schematic diagram of the mechanism of myofascial trigger points and treatment options. The initiating mechanisms of myofascial trigger points are shown in blue with the downstream events in dark blue. The treatment for myofascial pain is shown in red with the pathways of their action shown in dark red. The arrows indicate how one feature causes another. The square at the ends of lines indicates inhibition of the end feature by the preceding feature. The myofascial trigger point is initiated by a combination of chronic load on the muscle which caused microtubule proliferation which increases ROS production and a decreased ability to remove ROS. The increase of ROS increases ryanodine receptors open probability, hence increasing calcium which results in contraction and deformation of the microtubule network resulting in more ROS production. This is the key positive feedback loop. Psychological stress can contribute to this as it reduces mitochondrial content and increase ROS production in cells. The contraction restricts blood flow resulting in local ischemia/hypoxia that results in muscle damage and the inflammatory response. Pain is caused by the activation of nociceptors by a decreased pH (ASIC channels), increased ROS (TRPV1 channels), and substance P. When depolarized, nociceptive neurons release CGRP which increases the amount of and response to acetylcholine in the neuromuscular junction, which can cause additional contraction. This provided a second positive feedback loop. Treatments such as lidocaine and capsaicin block nociception. Other treatments such as massage and cold laser therapy might increase circulation or reduce oxidative stress. Furthermore, treatments that induce stretching/contraction such as needling, electrical stimulation, stretching, and exercise increase calcium local to high enough concentrations (>10 μM) transiently that induce microtubule depolymerization. Finally, the application of topical or injected thiocolchicine has been shown to reduce myofascial pain. Abbreviations: GSH (glutathione), ROS (reactive oxygen species), NADPH (nicotinamide adenine dinucleotide phosphate), RyR (ryanodine receptors), [Ca2+] (calcium concentration), [H+] (proton concentration), ATP (adenosine triphosphate), TRPV1 (transient receptor potential cation channel subfamily V member 1 or capsaicin receptor), ASIC (acid-sensing ion channel), CGRP (calcitonin gene related peptide), ACH (acetylcholine), ACHe (acetylcholinesterase), and ACHR (acetylcholine receptor).