Pituitary Adenylate Cyclase-Activating Polypeptide Is Required for the Development of Spinal Sensitization and Induction of Neuropathic Pain

Mabuchi, Tamaki; Shintani, Norihito; Matsumura, Shinji; Okuda‐Ashitaka, Emiko; Hashimoto, Hitoshi; Muratani, Tadatoshi; Minami, Toshiaki; Baba, Akemichi; Ito, Seiji

doi:10.1523/jneurosci.0983-04.2004

Cited by 114 publications

(115 citation statements)

References 37 publications

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“…Specifically, in Rgs9KO NAc, the early response to DMI induces the expression of genes encoding ion channels, transcription factors, neuronal guidance/differentiation, and signal transduction molecules known to be involved in several forms of pain and/or antidepressant drug actions. For example, mice lacking the adenylate cyclase-activating polypeptide 1 (Adcyap1) do not develop inflammatory or neuropathic pain and exhibit depression-like behaviors (28,57). We show a reduction of Adcyap1 expression in the NAc of Rgs9KO mice that respond to DMI treatment, supporting the hypothesis that reduction of ADCYAP1 activity prevents pain-like (E, Right) The table lists some of these genes with the corresponding fold changes.…”

Section: Resultssupporting

confidence: 62%

“…RNA-seq analyses reveal that chronic DMI alters expression of a number of genes, including those encoding GPCRs, ion channels, adenylyl cyclase targets, and components of the Wnt signaling pathway-several of which have been shown to play a prominent role in nociceptive transmission, mood disorders, and antidepressant drug actions. Differential gene-expression analysis revealed the down-regulation of many genes with DMI treatment after SNI in Rgs9KO mice compared with wild-type controls, including Adcyap1 and Bdnf, for which reduced function is associated with reduced neuropathic pain sensitivity (28,29), and Adcy1, the deletion of which reduces mechanical allodynia and inflammatory pain sensitivity (41). The expression of regulator of neurite outgrowth neuritin 1 (Nrn1), a gene that is stimulated by Bdnf and is implicated in antidepressant actions (42,43) and diabetic neuropathy (44), is also altered.…”

Section: Discussionmentioning

confidence: 99%

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

Mitsi

Terzi

Purushothaman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Resultssupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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

Mitsi

Terzi

Purushothaman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Others also showed that PACAP might play a key role in spinal sensitization, and therefore, in the development of neuropathic pain [8,25] through PAC1 receptor activation in the dorsal root ganglia [6,20]. Furthermore, PACAP is likely to have a pivotal pro-nociceptive function in animal models of migraine and also in human migraneurs [29,46,54].…”

Section: Discussionmentioning

confidence: 99%

Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions

et al. 2013

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a b s t r a c tPituitary Adenylate-Cyclase Activating Polypeptide (PACAP) and Tac1 gene-encoded tachykinins (substance P: SP, neurokinin A: NKA) are expressed in capsaicin-sensitive nerves, but their role in nociception, inflammation and vasoregulation is unclear. Therefore, we investigated the function of these neuropeptides and the NK 1 tachykinin receptor (from Tacr1 gene) in the partial sciatic nerve ligationinduced traumatic mononeuropathy model using gene deficient (PACAP −/− , Tac1 −/− , and Tacr1 −/− ) mice. Mechanonociceptive threshold of the paw was measured with dynamic plantar aesthesiometry, motor coordination with Rota-Rod and cutaneous microcirculation with laser Doppler imaging. Neurogenic vasodilation was evoked by mustard oil stimulating sensory nerves. In wildtype mice 30-40% mechanical hyperalgesia developed one week after nerve ligation, which was not altered in Tac1−/− and Tacr1mice, but was absent in PACAP −/− animals. Motor coordination of the PACAP −/− and Tac1 −/− groups was significantly worse both before and after nerve ligation compared to their wildtypes, but it did not change in Tacr1−/− mice. Basal postoperative microcirculation on the plantar skin of PACAP −/− mice did not differ from the wildtypes, but was significantly lower in Tac1 −/− and Tacr1 −/− ones. In contrast, mustard oil-induced neurogenic vasodilation was significantly smaller in PACAP −/− mice, but not in Tacr1 −/− and Tac1 −/− animals. Both PACAP and SP/NKA, but not NK 1 receptors participate in normal motor coordination. Tachykinins maintain basal cutaneous microcirculation. PACAP is a crucial mediator of neuropathic mechanical hyperalgesia and neurogenic vasodilation. Therefore identifying its target and developing selective, potent antagonists, might open promising new perspectives for the treatment of neuropathic pain and vascular complications.

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“…53 Capsaicin elevates PACAP in rat cerebrospinal fluid in vivo, 54 suggesting that PACAP may be released from activated C-fibers in the spinal cord. In PACAP gene knockout mice (Adcyap1 Ϫ/Ϫ ), inflammatory pain disappears 55 and PACAP promotes the functional coupling of neuronal NO-synthase to NMDA receptors. This leads to NO production in superficial layers of the dorsal horn in the spinal cord 55 and late-onset, transcriptionaland activity-dependent central sensitization.…”

Section: The Central Actions Of Pacapmentioning

confidence: 99%

“…In PACAP gene knockout mice (Adcyap1 Ϫ/Ϫ ), inflammatory pain disappears 55 and PACAP promotes the functional coupling of neuronal NO-synthase to NMDA receptors. This leads to NO production in superficial layers of the dorsal horn in the spinal cord 55 and late-onset, transcriptionaland activity-dependent central sensitization. 56 PAC 1 receptor knockout mice have a decreased response in nociceptive behavior after a formalin test, 57 which is a model of inflammatory nociception.…”

Section: The Central Actions Of Pacapmentioning

confidence: 99%

The PACAP Receptor: A Novel Target for Migraine Treatment

2010

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Summary:The origin of migraine pain has not yet been clarified, but accumulating data point to neuropeptides present in the perivascular space of cranial vessels as important mediators of nociceptive input during migraine attacks. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present in sensory trigeminal neurons and may modulate nociception at different levels of the nervous system. Human experimental studies have shown that PACAP-38 infusion induces marked dilatation of extracerebral vessels and delayed migraine-like attacks in migraine patients. PACAP selectively activates the PAC 1 receptor, which suggests a possible signaling pathway implicated in migraine pain. This review summarizes the current evidence supporting the involvement of PACAP in migraine pathophysiology and the PAC 1 receptor as a possible novel target for migraine treatment.

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Pituitary Adenylate Cyclase-Activating Polypeptide Is Required for the Development of Spinal Sensitization and Induction of Neuropathic Pain

Cited by 114 publications

References 37 publications

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

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

Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions

The PACAP Receptor: A Novel Target for Migraine Treatment

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