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.