Following the resolution of a severe inflammatory injury in rodents, administration of muopioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3-10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of "high-sensitizers" prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.
Bibliographical noteFunding Information:
B.K.T. was supported by NIH R01NS45954. We thank Tony Yaksh for advice in adapting the MHI-model to mice, Dr. Richard Charnigo and the Center for Clinical and Translational Sciences (CCTS) at the University of Kentucky for assistance with the statistics, Michael C. Rowbotham for comments on the protocol, and Karen-Lisa Hilsted for practical assistance with the protocol and the subjects for their valuable help. The CCTS is supported by NCRR UL1RR033173.
© 2015 Pereira et al.