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P2X3 receptors are involved with several pain conditions. Muscle pain induced by static contraction has an important socioeconomic impact. Here, we evaluated the involvement of P2X3 receptors on mechanical muscle hyperalgesia and neutrophil migration induced by static contraction in rats. Also, we evaluated whether static contraction would be able to increase muscle levels of TNF-α and IL-1β. Male Wistar rats were pretreated with the selective P2X3 receptor antagonist, A-317491, by intramuscular or intrathecal injection and the static contraction-induced mechanical muscle hyperalgesia was evaluated using the Randall-Selitto test. Neutrophil migration was evaluated by measurement of myeloperoxidase (MPO) kinetic-colorimetric assay and the cytokines TNF-α and IL-1β by enzyme-linked immunosorbent assay. Intramuscular or intrathecal pretreatment with A-317491 prevented static contraction-induced mechanical muscle hyperalgesia. In addition, A-317491 reduced static contraction-induced mechanical muscle hyperalgesia when administered 30 and 60 min of the beginning of static contraction, but not after 30 and 60 min of the end of static contraction. Intramuscular A-317491 also prevented static contraction-induced neutrophil migration. In a period of 24 h, static contraction did not increase muscle levels of TNF-α and IL-1β. These findings demonstrated that mechanical muscle hyperalgesia and neutrophil migration induced by static contraction are modulated by P2X3 receptors expressed on the gastrocnemius muscle and spinal cord dorsal horn. Also, we suggest that P2X3 receptors are important to the development but not to maintenance of muscle hyperalgesia. Therefore, P2X3 receptors can be pointed out as a target to musculoskeletal pain conditions induced by daily or work-related activities.

Among the types of pain that affect people throughout their lives, muscle pain, specially the one induced by sustained isometric contraction, is one of the most prevalent and has an important socio-economic impact. However, despite their clinical relevance, the molecular mechanisms involved in the development of muscle pain induced by sustained isometric contraction are unknown. This is mainly due to the absence of a more realistic experimental model that has a good degree of prediction of pharmacological control of pain. Therefore, the aim of this study was to develop a new model of muscle hyperalgesia induced by sustained isometric contraction in Wistar rats.The sustained isometric contraction was performed by the electrical stimulation directly to the belly of the gastrocnemius muscle of rats and the parameters were 19 millisecond of pulse duration, frequency of 50Hz, and intensity of 1.6 volts (V) for a period of 1 hour.Randall Selitto method was used to measure muscular hyperalgesia 30 minutes until 48 hours after the finish of sustained isometric contraction. This protocol induced mechanical muscle hyperalgesia for one hour and, after two hours, the responses were similar to the baseline. These responses were significantly higher than those induced by stimulation 1.6V for 15 and 30 minutes, 0.5 and 1.0 V for 1h or sham. We also demonstrated that the mechanical muscle hyperalgesia induced by sustained isometric contraction was blocked by dexamethasone, indicating the inflammatory nature of this new model, supported by the presence of inflammatory cells in muscle tissue, confirmed by histological analysis. Together, these data suggest that this new model of muscle hyperalgesia approaching a condition closest to the actual found in muscle pain resulting from daily activities, besides having a great scientific potential for the study of pathophysiological mechanisms involved in muscle pain related to contraction sustained isometric.

Molecular mechanisms involved in the development of muscle pain induced by static contraction are not completely elucidated. This study aimed to evaluate the involvement of the transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1) receptors expressed in peripheral and central terminals of primary afferents projected to gastrocnemius muscle and spinal cord in muscle pain induced by static contraction. An electrical stimulator provided the contraction of rat gastrocnemius muscle and mechanical muscle hyperalgesia was quantified through the pressure analgesimeter Randall-Selitto. AMG9810 and HC030031 were used. When administered in ipsilateral, but not contralateral gastrocnemius muscle, drugs prevented mechanical muscle hyperalgesia induced by static contraction. Similar results were obtained by intrathecal administrations. We propose that, in an inflammatory muscle pain, peripheral and central TRPV1 and TRPA1 work together to sensitize nociceptive afferent fibers, and that TRPV1 and TRPA1 receptors are potential target to control inflammatory muscle pain.