It is well known that pain can heighten sensitivity to stimuli that signal threat in most species. In rodents, exposure to predator odor, such as 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), induces anxiety and alters pain sensitivity. This study explored the effect of predator odor stress on mechanical pain sensitivity in a rat model of acute inflammatory pain induced by suboptimal doses of Complete Freund's Adjuvant (CFA). Male Sprague-Dawley rats were injected intraplantarly with 50% or 25% (v/v) of CFA in the hindpaw and then exposed the next day to 5 minutes of either 10% TMT (synthetic fox urine) or a neutral odor. Both groups showed reduced paw withdrawal thresholds in the von Frey test. However, TMT-exposed rats displayed persistent mechanical hypersensitivity, which never returned to baseline (pre-CFA) levels when compared to CFA-rats exposed to the neutral odor or control rats exposed to TMT. In addition, TMT exposure after CFA induced greater anxiety-like behavior in the elevated plus maze without affecting locomotor activity in the open field or altering learned responses in a backward paired shock-tone conditioning task. Finally, systemic administration of a CCK2 antagonist before exposure to TMT partially rescued the mechanical hypersensitivity in these animals but had little effect on CFA-treated rats exposed to the neutral odor. These results suggest that naturalistic stress can lead to a long-lasting nociceptive sensitization that extends beyond the duration of the initial inflammatory injury. Our findings also highlight the importance of CCK2 signaling as a potential mediator of and therapeutic target for stress-induced pain hypersensitivity.
Author Keywords: allodynia, CCK, CFA, mechanical sensitivity, stress, TMT