Lateralized kappa opioid receptor signaling from the amygdala central nucleus promotes stress-induced functional pain

Abstract

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.

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

“…Descending noradrenergic pathways remain intact after nerve injury but are hypoactive (Hirschberg et al., ; Hughes, Hickey, Hulse, Lumb, & Pickering, ; Patel, Qu, Xie, Porreca, & Dickenson, ), and DNIC are restored following spinal delivery of a noradrenaline reuptake inhibitor (Bannister et al., ). Chronic pain states can also be associated with increased descending facilitation, largely mediated via spinal 5‐HT 2A and 5‐HT 3 receptors (Patel & Dickenson, ; Suzuki, Rahman, Hunt, & Dickenson, ), and enhanced excitatory drive can mask inhibitory signalling (Bannister et al., ; Nation et al., ; Okada‐Ogawa, Porreca, & Meng, ; Phelps, Navratilova, Dickenson, Porreca, & Bannister, ).…”

Kappa opioid signaling in the right central amygdala causes hind paw specific loss of diffuse noxious inhibitory controls in experimental neuropathic pain

“…Increased endogenous kappa opioid receptor (KOR) signaling in the brain is part of the canonical stress response [18; 35; 39]. In a rat model of functional pain, stress-induced allodynia and loss of DNIC was blocked by nor-BNI, a KOR antagonist given systemically or in the right central amygdala (RCeA) [27], suggesting that KOR signaling in the RCeA drives facilitation of pain, and loss of DNIC, in uninjured but sensitized states. However, when allodynia is present in the absence of an external psychological stressor, as is the case in neuropathic pain, it is unknown whether the loss of the DNIC response is similarly caused by increased RCeA KOR signaling.…”

“…A difference between the loss of DNIC observed in experimental neuropathic versus functional pain is the need for an external stressor (such as bright lights) prior to testing DNIC and allodynia in the injury-free model [27]. Stress is known to activate kappa opioid signaling through release of endogenous dynorphin in the brain, including the amygdala [18; 35].…”

Peripheral Kappa Opioid Receptor Signaling Takes on a Central Role

“…While both the analgesic and the addictive pharmacological actions of morphine and its derivatives can solely be accounted for by MORs, DORs have additionally been attributed anxiolytic and anti-depressive properties. Paradoxically, KOR signaling has been associated with both analgesia and allodynia, i.e., pain in response to nonnoxious stimulation, and its activation in brain centers is linked to aversion and the negative component of pain, stress responses, and drug reinstatement (Nation et al, 2018) (Figure 1).…”