Delayed Nociceptive Response Following Cold-Water Swim in the Formalin Test: Possible Mechanisms of Action

Exposure of animals to aversive events produces stress-induced analgesia. A common method of producing stress in animals is the cold-water swim (CWS). The present series of experiments examines the effect of CWS on tonic pain, as measured by the formalin test, and explores possible mechanisms of action. Experiment 1 demonstrates that a 3.5-min swim in 2°C water produces a delayed nociceptive response (DNR), characterized by a prolonged period of no formalin responding which then begins and continues during the time when control animals, which have not received the CWS, are finished responding. The delayed response begins at 50–60 min postformalin injection, peaks at 80 min, and is still present at 120 min. Experiment 2 indicates that paw temperature effects are not responsible for the DNR, although core body temperature effects are a possible mechanism. However, systematic delays in the formalin injection following the CWS (Experiment 3) drastically altered the DNR even though core body temperature remained unchanged, suggesting that a decrease of core body temperature is insufficient to account for the DNR. Experiment 4 demonstrates that the NMDA antagonist MK-801 administered prior to the CWS dramatically reduces the DNR. The present experiment is the first study that reports a delay as long as 60 min in pain responding. It is concluded that the delayed response to formalin injection is the result of complex interactions involving peripheral mechanisms and central neuronal plasticity in which activity initiated by a noxious input persists after the cessation of the input as a consequence of a stressful event such as the cold-water swim.