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.

Addressing the correspondents’ second concern, we did not assess the integrity of fracture healing in the mice exposed to anti-HMGB1; the choice of that reagent was to probe the mechanism involved in initiating the innate immune response to surgery. Were we to advocate the use of anti-HMGB1 as a treatment we agree that it would be necessary to assess fracture healing as well as other chromatin actions.

We hope that our rebuttal has allayed the correspondents’ remaining concerns about our study.