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In Reply: We thank the correspondents for their interest in our work and the Journal for the opportunity to respond. Addressing the first concern, while we have done studies in rats with this model,1,2 in our recently published study3 we used mice, a species that we have reported on in this behavioral paradigm many times before.4–12 In addition, this behavioral paradigm has been used by other laboratories to good effect.13,14 Next, we need to clarify a timeline issue that appears to have confused the correspondents. As indicated in figure 1 and elaborated in the narrative (p. 1162, first column) the mice are only exposed to a foot-shock during the training session before surgical manipulation. Therefore, possible surgical injury to nociceptive nerves that transmit the foot-shock does not pertain. The correspondents’ concern about the influence of surgery-induced nociception on aversive motile behavior should be allayed by the facts that (1) we routinely provide postoperative analgesia with buprenorphine response (p. 1161, second column), and, (2) motility is unaffected by surgery.6 We disagree with the correspondents’ contention we may be overstating the effect of surgery in our freezing time experiments. Were the surgical phenotype to be affected by pain-related immobility, then we should see more rather than less freezing time; therefore, if anything, we may be understating the influence of surgery on freezing time. fracture model is inappropriate, and may overstate the effect of neurodevelopment impairment and cognitive decline. The second concern regards the healing of the tibia fracture after the neutralization of high-mobility group box 1 protein and the depletion of bone marrow-derived macrophages, as the activation of the immune system and the inflammatory response is essential for tissue repair cascade, following any injury. We are wondering whether the authors have observed the fracture healing process in their experiment.

Is It Appropriate to Use Fear Conditioning to Assess Behavior Impairment in Fracture Rat Models?