Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice

Markovics, Adrienn; Kormos, Viktória; Gaszner, Balázs; Lashgarara, Arvin; Szöke, Éva; Sándor, Katalin; Szabadfi, Krisztina; Tuka, Bernadett; Tajti, János; Szolcsányi, Janós; Pintér, Erika; Hashimoto, Hitoshi; Kun, József; Reglődi, Dóra; Helyes, Zsuzsanna

doi:10.1016/j.nbd.2011.10.010

Cited by 152 publications

(170 citation statements)

References 82 publications

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“…The C57BL/6J strain was chosen to match our previous studies with wild-type mice (Kaiser et al, 2012) and the transgenic hRAMP1 mice, which are on a predominantly C57BL/6J background (Recober et al, 2009b). The CD1 strain was chosen based on blood flow observations suggesting the possibility these mice might be more responsive to sensory neuropeptides than C57BL/6J mice (Markovics et al, 2012;Botz et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms

Mason¹,

et al. 2016

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The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. Although migraine can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the CNS, we used CGRP-induced light-aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal) injection of CGRP resulted in light-aversive behavior in wild-type CD1 mice similar to aversion seen previously after central (intracerebroventricular) injection. The phenotype was also observed in C57BL/6J mice, although to a lesser degree and with more variability. After intraperitoneal CGRP, motility was decreased in the dark only, similar to motility changes after intracerebroventricular CGRP. In addition, as with intracerebroventricular CGRP, there was no general increase in anxiety as measured in an open-field assay after intraperitoneal CGRP. Importantly, two clinically effective migraine drugs, the 5-HT 1B/D agonist sumatriptan and a CGRP-blocking monoclonal antibody, attenuated the peripheral CGRP-induced light aversion and motility behaviors. To begin to address the mechanism of peripheral CGRP action, we used transgenic CGRP-sensitized mice that have elevated levels of the CGRP receptor hRAMP1 subunit in nervous tissue (nestin/hRAMP1). Surprisingly, sensitivity to low light was not seen after intraperitoneal CGRP injection, but was seen after intracerebroventricular CGRP injection. These results suggest that CGRP can act in both the periphery and the brain by distinct mechanisms and that CGRP actions may be transmitted to the CNS via indirect sensitization of peripheral nerves.

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Section: Resultsmentioning

confidence: 99%

Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms

Mason¹,

et al. 2016

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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]. Others suggested that the peripheral nociceptive responses elicited by intradermally administered PACAP are mainly mediated through the VPAC receptors [45].…”

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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“…Animal studies supported these observations: PACAP38 was present in the trigeminal ganglion and caudal trigeminus nucleus, and plasma PACAP levels increased after electrical stimulation of the trigeminal ganglion [ 38 ] or after dural stimulation in cats [ 21 ]. PACAP knockout animals showed reduced responses to nitroglycerol [ 39 ].…”

Section: Migrainementioning

confidence: 58%

PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

Reglődi

Helyes

Németh

et al. 2016

Current Topics in Neurotoxicity

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with wide distribution and diverse effects. Its presence has not only been revealed in the nervous system and peripheral organs, but also in the blood and other biological fl uids. Although PACAP is rapidly cleaved in the blood by peptidases, increasing number of evidence has been published in the last 10 years that show alterations of PACAP levels in different pathological conditions. The present review summarizes results obtained in the human blood and other fl uids under normal, physiological and pathological conditions with clinical relevance, such as pregnancy and delivery, as well as in several diseases. Most clinical data have been obtained so far in neurological diseases, such as Alzheimer's disease, migraine, traumatic brain injury, multiple sclerosis, and cerebral hemorrhage, but some other diseases have also been shown to be accompanied by alterations of PACAP levels. These results indicate that the altered levels may have diagnostic and/or prognostic values in several diseases.

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Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice

Cited by 152 publications

References 82 publications

Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms

Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms

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

PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

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