resiniferatoxin and Musculoskeletal-Pain

The exacerbation of musculoskeletal pain by stress in humans is modeled by the musculoskeletal hyperalgesia in rodents following a forced swim. We hypothesized that stress-sensitive corticotropin releasing factor (CRF) receptors and transient receptor vanilloid 1 (TRPV1) receptors are responsible for the swim stress-induced musculoskeletal hyperalgesia. We confirmed that a cold swim (26 °C) caused a transient, morphine-sensitive decrease in grip force responses reflecting musculoskeletal hyperalgesia in mice. Pretreatment with the CRF2 receptor antagonist astressin 2B, but not the CRF1 receptor antagonist NBI-35965, attenuated this hyperalgesia. Desensitizing the TRPV1 receptor centrally or peripherally using desensitizing doses of resiniferatoxin (RTX) failed to prevent the musculoskeletal hyperalgesia produced by cold swim. SB-366791, a TRPV1 antagonist, also failed to influence swim-induced hyperalgesia. Together these data indicate that swim stress-induced musculoskeletal hyperalgesia is mediated, in part, by CRF2 receptors but is independent of the TRPV1 receptor.

Topics: Acenaphthenes; Analgesics; Analysis of Variance; Animals; Body Weight; Cold Temperature; Disease Models, Animal; Diterpenes; Female; Hyperalgesia; Mice; Morphine; Muscle Strength; Musculoskeletal Pain; Pain Measurement; Peptide Fragments; Peptides, Cyclic; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Swimming; TRPV Cation Channels

Inactivation of transient receptor potential vanilloid-1 (TRPV1) receptors is one approach to analgesic drug development. However, TRPV1 receptors exert different effects on each modality of pain. Because muscle pain is clinically important, we compared the effect of TRPV1 ligands on musculoskeletal nociception to that on thermal and tactile nociception. Injected parenterally, capsaicin had no effect on von Frey fiber responses (tactile) but induced a transient hypothermia and hyperalgesia in both the tail flick (thermal) and grip force (musculoskeletal) assays, presumably by its agonistic action at TRPV1 sites. In contrast, resiniferatoxin (RTX) produced a chronic (>58 days) thermal antinociception, consistent with its reported ability to desensitize TRPV1 sites. In the same mice, RTX produced a transient hypothermia (7 hours) and a protracted (28-day) musculoskeletal hyperalgesia in spite of a 35.5% reduction in TRPV1 receptor immunoreactivity in muscle afferents. Once musculoskeletal hyperalgesia subsided, mice were tolerant to the hyperalgesic effects of either capsaicin or RTX whereas tolerance to hypothermia did not develop until after 3 injections. Musculoskeletal hyperalgesia was prevented but not reversed by SB-366791, a TRPV1 antagonist, indicating that TRPV1 receptors initiate but do not maintain hyperalgesia. Injected intrathecally, RTX produced only a brief musculoskeletal hyperalgesia (2 days), after which mice were tolerant to this effect.. The effect of TRPV1 receptors varies depending on modality and tissue type, such that RTX causes thermal antinociception, musculoskeletal hyperalgesia, and no effect on tactile nociception in healthy mice. Spinal TRPV1 receptors are a potential target for pain relief as they induce only a short musculoskeletal hyperalgesia followed by desensitization.

Topics: Animals; Diterpenes; Female; Hyperalgesia; Mice; Musculoskeletal Pain; Neurotoxins; Pain Measurement; TRPV Cation Channels