Many patients suffer from chronic pain in the absence of identifiable injury. Such pains are termed ?functional? and include irritable bowel syndrome, temporomandibular joint disorder, fibromyalgia, migraine and others. Functional pain patients experience pain free periods that are interrupted by attacks of pain that can persist for variable periods of time. The chronification of these pain disorders has been linked to the number and frequency of attacks suggesting that repeated nociceptive episodes promote and maintain a state of central sensitization that reflects increased vulnerability to future attacks. Functional pain patients commonly identify stress as a key trigger of pain episodes but neurobiological mechanisms remain to be determined. In this project, we test the novel hypothesis that in sensitized states, stress-induced kappa opioid receptor (KOR) signaling in the amygdala promotes functional pain responses. We have developed an injury-free rodent model of stress-related functional pain based on hyperalgesic priming with opioids. Opioids have been shown to produce opioid-induced hyperalgesia (OIH) in humans and in animals. OIH is characterized by generalized tactile and thermal hyperalgesia, decreased nociceptive thresholds, increase temporal summation, and a loss of descending noxious inhibitory controls (DNIC). Following resolution of OIH, and in the absence of stress, animals have normal pain responses. Hyperalgesic priming, however, produces a state of latent sensitization so that animals previously exposed to morphine are now prone to stress-induced hyperalgesia and a loss of DNIC that is prevented by blockade of KOR signaling within the central nucleus of the amygdala (CeA). Our electrophysiological data support a KOR-mediated disinhibition of CeA neurons that promote pain. We will use advanced behavioral and electrophysiological approaches with optogenetic and chemogenetic methods to demonstrate that activation of CeA KOR neurons in control, unprimed mice promotes pain-related responses (Specific Aim 1). These studies will establish the neural circuitry within the amygdala that may underlie a novel KOR-mediated pronociceptive CeA output that is engaged through disinhibition.
Specific Aim 2 will determine if exogenous activation of the CeA KOR circuit results in amplified pain responses following priming- induced latent sensitization.
In Specific Aim 3 we will determine whether blockade of stress-induced endogenous CeA KOR signaling reduces pain responses following priming-induced latent sensitization. The proposed studies will characterize a previously unknown stress-related KOR mediated hyperalgesic circuit from CeA and determine how this circuit may promote decreased resilience to stress. Importantly, these studies may unravel mechanisms for therapeutic interventions in stress-related functional pain disorders through an actionable molecular target. KOR antagonists are currently in development.

Public Health Relevance

The amygdala integrates external sensory and internal emotional/affective information to allow appropriate behavioral responses. Increased output from the central nucleus of the amygdala (CeA) has been shown to promote pain and stress responses. This project identifies and characterizes a novel kappa opioid receptor/dynorphin circuit in the CeA that may amplify stress-induced pain in sensitized functional pain conditions. This mechanism can lead to novel therapies for the treatment of functional pain disorders including irritable bowel syndrome, fibromyalgia, migraine, temporomandibular joint disorder and others.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Oshinsky, Michael L
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University of Arizona
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Thompson, Jeremy M; Yakhnitsa, Vadim; Ji, Guangchen et al. (2018) Small conductance calcium activated potassium (SK) channel dependent and independent effects of riluzole on neuropathic pain-related amygdala activity and behaviors in rats. Neuropharmacology 138:219-231
Ji, Guangchen; Yakhnitsa, Vadim; Kiritoshi, Takaki et al. (2018) Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats. Mol Pain 14:1744806918804441
Kiritoshi, Takaki; Neugebauer, Volker (2018) Pathway-Specific Alterations of Cortico-Amygdala Transmission in an Arthritis Pain Model. ACS Chem Neurosci 9:2252-2261