The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional
pain syndromes. Because the
dynorphin/
kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional
pain. Male, Sprague-Dawley rats were primed for 7 days with systemic
morphine resulting in
opioid-induced
hyperalgesia. Fourteen days after priming, when
hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after
capsaicin injection in the forepaw (conditioning stimulus).
Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in
morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist,
nor-binaltorphimine (
nor-BNI). Microinjection of
nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in
morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral
nor-BNI in the rostral ventromedial medulla. Stress increased
dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although
morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced
dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition.
Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional
pain disorders.