Increased amygdala kappa opioid receptor signaling following stress promotes descending facilitation and leads to loss of diffuse noxious inhibitory controls (DNIC) (2017)

Diffuse noxious inhibitory controls (DNIC) is a pain modulatory system by which one painful stimulus is inhibited by another painful stimulus applied to a remote area of the body. This phenomenon, commonly described as “pain inhibits pain”, is critically important for prioritization of pain signals allowing for selection of appropriate behavioral responses. DNIC is measured by the concurrent application of a noxious conditioning stimulus and a noxious test stimulus. The application of the conditioning stimulus increases the pain threshold to the test stimulus when there is an efficient DNIC response. In human studies, DNIC is referred to as conditioned pain modulation (CPM). A diminished CPM response has been observed in pain states that do not involve injury (i.e., functional pain conditions) including fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, and migraine. Many of these functional pain disorders are aggravated or triggered by stress. In migraineurs, medications used to treat migraine, including opioids can cause an increase in headache frequency, called medication overuse headache (MOH). MOH is also associated with a loss of CPM. The loss of the DNIC/CPM response is interpreted as a neural adaptation involving changes in descending pain inhibitory or facilitation pathways. We have previously demonstrated that priming animals with morphine produces a loss of the DNIC response that can be reversed by inactivation of the rostral ventromedial medulla (RVM) suggesting enhanced descending facilitation that may mask inhibition (i.e., net facilitation). In this study we investigated a potential circuit that may mediate enhanced facilitation possibly leading to a loss of DNIC. Dynorphin, the endogenous KOR ligand, has been shown to be a stress mediator and to promote aversiveness. We hypothesized that increased KOR signaling produces a lack of resilience to stress which may lead to increased susceptibility to increased facilitation promoting pain as with migraine. To model MOH rats were given morphine or vehicle continuously for seven days and two weeks after the end of treatment were exposed to stress from bright lights for one hour a day on two consecutive days. In order to investigate the role of KOR activation by endogenous agonists we gave rats nor‐BNI, a KOR antagonist, or vehicle one hour prior to each bright light stress session rats. Nor‐BNI or vehicle treatment was delivered either subcutaneously or through a cannula implanted in the central nucleus of the amygdala a part of the descending pain modulatory pathway. We found that morphine pretreatment caused a loss of DNIC that was restored by systemic nor‐BNI. Nor‐BNI given into the right CeN also restored the DNIC response in morphine pretreated rats. This suggests that the presence of a descending pain facilitatory influence mediated by stress‐induced KOR signaling that may be captured through the DNIC response. This mechanism may be significant in promoting functional pain disorders and could lead to the development of novel therapeutics. Support or Funding Information This work was supported by R01 DA 041809 and R01 NS 069575 from the NIH.