Algesic agents exciting muscle nociceptors

Morphologically, muscle nociceptors are free nerve endings connected to the CNS by thin myelinated (group III) or unmyelinated (group IV) afferent fibers. Not all of these endings are nociceptive; approximately 40% have a low mechanical threshold and likely fulfill non-nociceptive functions. Two chemical stimuli are particularly relevant as causes of muscle pain. The first is a drop in tissue pH, i.e. an increase in proton (H+) concentration. A large number of painful patho(physio)logical alterations of muscle tissue are associated with an acidic interstitial pH (e.g. tonic contractions, spasm, inflammation). The second important cause of muscle pain is a release of adenosine triphosphate (ATP). ATP is present in all body cells, but in muscle its concentration is particularly high. Any damage of muscle cells (trauma, necrotic myositis) is accompanied by a release of ATP from the cells. Therefore, ATP is considered a general pain stimulus by some. ATP and protons are relatively specific stimuli for muscle pain; in cutaneous pain they play a less important role. The numerous agents that are released in pathologically altered muscle include substances that desensitize mechanosensitive group IV receptors. Capsaicin has a long-lasting desensitizing action, brain-derived neurotrophic factor, and tumor necrosis factor-alpha, a short-lasting one. Most of the agents exciting group IV units (e.g. low pH, ATP, capsaicin) activate not only nociceptive endings but also non-nociceptive ones. The only substance encountered that excites exclusively nociceptive group IV receptors is nerve growth factor (NGF). In rat muscle chronically inflamed with complete Freund's adjuvant, most group IV endings are sensitized to mechanical (and to some) chemical stimuli. However, stimulants such as ATP, NGF, and solutions of low pH were found to be less effective in inflamed muscle. A possible explanation for this surprising finding is that in inflamed muscle the concentrations of ATP and NGF and H+ are increased. Therefore, experimental administration of these agents is a less effective stimulus.