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  • Based on the ability of CRF to modulate nociception we

    2019-09-11

    Based on the ability of CRF to modulate nociception, we hypothesized that stress leads to hyperalgesia by the activation of CRF1 and/or CRF2 receptors in the spinal cord. We tested this hypothesis using an acute forced swim as a widely used and easily reproducible stressor and grip force as a measure of musculoskeletal nociception that has proven sensitive to stress-induced hyperalgesia in rats (Imbe et al., 2010). Involvement of CRF receptors was examined using NBI-35965, a CRF1 receptor antagonist, and astressin 2B, a CRF2 receptor antagonist. Skeletal muscles are innervated by the same category of primary afferent C- and A∂-fibers as those used in the transmission of other nociceptive stimuli (Cavanaugh et al., 2009; Mense, 1992; O\'Connor and Cook, 1999). Transient receptor potential vanilloid 1 (TRPV1) receptors exert pro-nociceptive effects by activation of primary afferent C-fibers (Hoheisel et al., 2004) and Aδ- fibers (Churyukanov et al., 2012) innervating both skin and muscle (Hoheisel et al., 2004; Holzer, 1988; Light et al., 2008; Szallasi et al., 2007). While TRPV1 ligands have been found to have no effect on mechanical sensitivity in some models (Bishnoi et al., 2011a, 2011b), TRPV1 is crucial to the enhancement of nociception in many models of hyperalgesia (Chung et al., 2011; Fujii et al., 2008; Roberts et al., 2011; Szabo et al., 2005). To determine whether swim stress-induced musculoskeletal hyperalgesia is mediated by TRPV1 activity, we examined the sensitivity of stress-induced hyperalgesia to pretreatment with resiniferatoxin (RTX), a Pramipexole that desensitizes TRPV1 sites (Farkas-Szallasi et al., 1996; Goso et al., 1993; Iadarola and Mannes, 2011; Kissin and Szallasi, 2011; Szallasi and Blumberg, 1992; Szallasi et al., 1989) and to pretreatment with SB-366791, an antagonist at TRPV1 receptors (Varga et al., 2005).
    Material and methods
    Results
    Discussion Swim stress induces a transient musculoskeletal hyperalgesia in rats (Okamoto et al., 2012; Suarez-Roca et al., 2006a). The present study confirms the development of an identical hyperalgesia following daily swim stress in mice. Our study extends previous work in this area by showing that CRF2 receptors in the spinal cord area are important in the generation of this stress-induced musculoskeletal hyperalgesia, however, unlike other types of hyperalgesia, these signals are transmitted along spinal and primary afferent pathways that do not express TRPV1 receptors. In our studies, a 15-min swim in cold (26 °C) water caused hyperalgesia in mice when measured using the grip force assay, consistent with previous work in rats (Suarez-Roca et al., 2006a). Just as hyperalgesia in rats was validated by attenuation of the decrease in grip force by diclofenac and by morphine (Suarez-Roca et al., 2006a), we found that morphine attenuated the decrease in grip force in mice. The sensitivity to morphine supports the conclusion that stress-induced decreases in grip force measured in the present study resulted from nociception rather than weakness. In addition to musculoskeletal hyperalgesia, we observed that swim stress induced a simultaneous antinociception in the tail flick assay consistent with previous studies of thermal nociception measured using either the tail flick (Grisel et al., 1993) or hot plate assays (Marek et al., 1993; Mogil et al., 1996; Vaccarino and Clavier, 1997). Each modality of pain is influenced differently by stress allowing stress to induce a decrease in thermal nociception (antinociception) in the same mice as those in which decreases in grip force (musculoskeletal hyperalgesia) were observed. In previous studies of stress-induced hyperalgesia, differential modulation of muscle and cutaneous thermal nociceptive pathways was suggested by the finding that milnacipran decreased swim-induced muscle hyperalgesia (grip strength) without affecting cutaneous thermal hyperalgesia (hot plate) in rats (Suarez-Roca et al., 2006a).