Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Abstract

Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous k-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous k-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the m-opioid agonist morphine) or by the k-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and k-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous k-opioid systems, in mediating acute pain-related behavioral depression in rats.

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

“…Insofar as drug-induced facilitation of ICSS is predictive of abuse potential (Negus and Miller, 2014), these results are consistent with the abuse liability of opioid analgesics (Gutstein and Akil, 2006). These results are also consistent with other data that suggest reciprocal effects of m-opioid analgesics and pain states on brain reward circuitry and behaviors such as ICSS that rely on brain reward circuitry (Leknes and Tracey, 2008;Leitl et al, 2014).…”

Association of In Vivo κ-Opioid Receptor Availability and the Transdiagnostic Dimensional Expression of Trauma-Related Psychopathology

“…11,17,18,49,50 Of particular interest are reports linking the mesocorticolimbic dopamine and activated dynorphin/KOR systems to dysphoric symptoms. Specifically, ventral tegmental area dopamine neurons receive inputs from dynorphinergic neurons and express KORs, and activation of these KORs depresses neuronal activity and dopamine release, 49,51 which may consequently contribute to the development of loss symptoms. These data also suggest that severe stress exposure can trigger delayed but more sustained changes in KOR systems that increase vulnerability to loss symptoms at later times.…”

Brain Neuroplastic Changes Accompany Anxiety and Memory Deficits in a Model of Complex Regional Pain Syndrome

“…For instance, there is evidence of anxiety 49,50 and attention deficits 51–55 in rodent models of pain, in addition to changes in mood 50,56,57 and overall cognitive function 58–60 . Similar to what is seen in patients, 61 some of these conditions subside once the pain is ameliorated.…”