RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Abstract

The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.desipramine | duloxetine | HDAC5 | spared nerve injury | gene expression R egulator of G-protein signaling 9-2 (RGS9-2) is an intracellular modulator of G-protein-coupled receptor (GPCR) function, which is expressed in medium spiny neurons and cholinergic interneurons of the striatum (1, 2). RGS9-2 influences the magnitude and time course of GPCR signaling by promoting GTPase activity of the Gα subunit and by preventing activation of Gα effectors (3). This modulation can also influence the duration of interactions between the Gβγ subunits and their effector molecules. In addition to Gα subunits, RGS9-2 interacts with several scaffolds and signal transduction proteins that affect its function, expression, and cellular localization. Interactions with the Gβ5 subunit and the adaptor protein R7BP determine the stability and cellular localization of RGS9-2, respectively (3, 4). Several recent studies have provided information on the regulation and function of RGS9-2 complexes in the striatum and how these complexes affect pharmacologic responses (2, 5, 6). In particular, RGS9-2 has been shown to modulate the actions of various psychotropic, antiparkinsonian, neuroleptic, and opiate analgesic drugs (1, 7). The nucleus accumbens (NAc) is a striatal brain region that is a major site of antidepressant drug action (8). Recent studies provided information on signal transduction events triggered by tricyclic antidepressants (TCAs) in NAc neurons and identified several second messengers, transcription factors, and epigenetic molecules involved in their therapeutic actions (9-11). TCAs, such as desipramine (DMI) and nortriptyline (NTL), and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) have also been used to treat neuropathic pain, a complex chronic disorder that is highly comorbid with anxiety and depression (12, 13) and is characterized by thermal hyperalgesia, mech...

Brain-Derived Neurotrophic Factor in the Mesolimbic Reward Circuitry Mediates Nociception in Chronic Neuropathic Pain

“…The NAc is an important brain region downstream of the VTA, and structural and functional plasticity in the NAc have been associated with chronic pain (12, 13, 23, 45–48). Thus, we investigated the functional role of VTA–NAc circuitry in modulating neuropathic pain.…”

Modulation of pain, nociception, and analgesia by the brain reward center

“…One of the key adaptations in these neurons concerns the expression and function of galanin receptor 1 (Schwartz et al, 2014). Recent work from our group using next-generation sequencing, also showed adaptations in the galaninergic system in the NAc of mice at one month after nerve injury (Mitsi et al, 2015). Notably, the galaninergic system dynamically modulates sensory transmission in the spinal cord under neuropathic pain states (Holmes et al, 2003).…”

“…In support of this hypothesis, we showed that RGS9 -knockout mice develop depression-like behaviors earlier than their wildtype controls (at six weeks after spared nerve injury, whereas wildtype mice show these behaviors at eight weeks). Importantly, genetic manipulations of RGS9-2 in the NAc did not affect the development or the intensity of mechanical allodynia (Mitsi et al, 2015). These data further support the hypothesis that neuropathic pain promotes long-term adaptations in the brain reward center.…”

Persistent neuropathic pain increases synaptic GluA1 subunit levels in core and shell subregions of the nucleus accumbens

“…The SNI model is widely used to study molecular changes in the brain in response to chronic pain [10, 11, 17, 33, 39]. SNI, however, can lead to both nerve injury and pain.…”