Evaluation of Cortical and Sub-Cortical Opioid-Sensitive Pain Neurocircuitry in Rodents

Abstract

Mu-opioid (MOR) and kappa-opioid receptors (KOR) are expressed throughout the pain pathways and in pain-related brain areas to provide endogenous pain control. MOR circuits in the anterior cingulate cortex (ACC) have been shown to modulate the affective qualities of pain, while KOR circuits are activated by stress and may promote or enhance affective and sensory aspects of pain. Functional connectively between the ACC and brainstem regions comprising the descending pain pathways has been observed in a number of pain neuroimaging studies in humans, but whether and how opioid activity in this cortical region participates in descending modulation is not well understood. Furthermore, investigations of casual opioid effects in a single brain area are not readily achievable in humans. Part I of these studies aim to determine whether microinjections of morphine into the rostral ventromedial medulla (RVM), or into 3 separate subdivision of the ACC, may selectively modulate affective and sensory aspects of acute and ongoing neuropathic pain in rats. We report that activation of MORs within specific rostral ACC circuits selective modulate affective dimensions of ongoing pain without altering sensory aspects. KORs have similar expression patterns to MORs in pain-related areas but may exert opposing effects, as KOR-dependent pathways may be involved in creating negative affective states. Signaling at KORs in the amygdala has been found to play a critical role in the stress response and may be promoting sensory and affective qualities of pain to functional pain syndromes. Part II of these studies aim to characterize KOR-expressing cells in the central nucleus of the amygdala (CeA) in order to help elucidate the mechanism by which KOR signaling in the CeA promotes pain. We report that KOR-expressing cells represent a novel subpopulation of neurons in the lateral central amygdala (CeL) which, through activation via an agonist, lead to enhanced pro-nociceptive effects. These data suggest that in an injured state, MOR agonists such as morphine, may reduce aversiveness and facilitate relief by differentially modulating the affective component of pain within specific rostral ACC circuits while KOR agonists act in an opposing manner by acting on a novel population of pro-nociceptive KOR+ cell types in the amygdala to promote hypersensitivity and pain aversiveness. KOR antagonist/MOR agonist compounds may provide new, safer therapies for stress-related and possibly other chronic pain conditions.