Amygdala kappa opioid system involvement in opioid relapse in pain states

ABSTRACT
Chronic pain is second only to bipolar disorder as the major cause of suicide among all medical illnesses,
where prevalence of depression ranges between 30 to 80%. The importance of this negative affect is reflected
in studies that show co-existing psychopathology increases pain intensity, pain-related disability and
susceptibility for opioid use disorder. Allostatic adaptations caused by chronic opioid drug exposure, diminish
reward, however, paradoxically, they reinforce drug-seeking behavior that contributes to the high rates of
opioid misuse and development of opioid use disorder in chronic pain patients. One of the opponent processes
to chronic drug administration is engagement of extra-hypothalamic stress systems, including increased
activity of corticotropin-releasing factor and dynorphin within the extended amygdala (which includes the
central nucleus of the amygdala, CeA). The extended amygdala integrates stress and reward systems to
produce drug withdrawal-induced negative affective states. Additionally, the lateral CeA responds
predominantly to painful stimuli being termed the ‘nociceptive amygdala’ and a circuit from the parabrachial
nucleus to the CeA was recently shown to be involved in aversive learning of noxious (painful) stimuli.
Dynorphin neurons are present in the lateral CeA, of which ~1/3 co-express corticotrophin releasing factor.
This brain region has been implicated in both drug consumption and pain. For example, administration the
kappa opioid receptor (KOR) antagonist nor-BNI into the CeA decreased excessive alcohol intake and chemo-
genetic silencing CeA dynorphin neurons reduced alcohol drinking. KOR signaling in the CeA was also shown
to contribute to chronic pain-induced aversion. Given the involvement of the CeA in aversive learning related to
ongoing pain, and the involvement of these neurons in drug-seeking behavior, the primary aim of our
application is to determine the extent amygdala KOR system contributes to increased drug-seeking behavior in
chronic pain. We will use a mouse model of opioid intravenous self-administration focusing on a reinstatement
paradigm that models relapse of drug-seeking behavior. This paradigm allows us to determine the extent KOR
systems contribute to stress-induced reinstatement. Our central hypothesis is that chronic pain states lead
to activation of KOR systems in the CeA that are involved in stress-induced reinstatement of opioid
drug-seeking behavior. Aim 1 of the proposal will determine the necessity and sufficiency of CeA dyn-KOR
system in negative reinforcement. Aim 2 will determine the sufficient and necessity of the CeA
dynorphin/kappa opioid system in reinstatement of opioid place preference. Aim 3 will determine the extent
stress-induced reinstatement of opioid self-administration is driven by the kappa opioid system in the CeA.

Grant Number: 5R01DA053752-05
NIH Institute/Center: NIH
Principal Investigator: CATHERINE CAHILL