Publications by authors named "Andrew F Russo"

78 Publications

Editorial: Calcitonin Gene-Related Peptide: Novel Biology and Treatments.

Front Physiol 2022 19;13:964568. Epub 2022 Jul 19.

Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.

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http://dx.doi.org/10.3389/fphys.2022.964568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344364PMC
July 2022

Stimulation of CGRP-expressing neurons in the medial cerebellar nucleus induces light and touch sensitivity in mice.

Neurobiol Pain 2022 Aug-Dec;12:100098. Epub 2022 Jun 23.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.

Calcitonin gene-related peptide (CGRP) is considered a major player in migraine pathophysiology. However, the location and mechanisms of CGRP actions in migraine are not clearly elucidated. One important question yet to be answered is: Does central CGRP signaling play a role in migraine? One candidate site is the cerebellum, which serves as a sensory and motor integration center and is activated in migraine patients. The cerebellum has the most CGRP binding sites in the central nervous system and a deep cerebellar nucleus, the medial nucleus (MN), expresses CGRP (MN). A previous study demonstrated that CGRP delivery into the cerebellum induced migraine-like behaviors. We hypothesized that stimulation of MN neurons might induce migraine-like behaviors. To test the hypothesis, we used an optogenetic strategy using mice to drive Cre-dependent expression of channelrhodopsin-2 selectively in CGRP neurons in the cerebellar MN. A battery of behavioral tests was done to assess preclinical behaviors that are surrogates of migraine symptoms, including light aversion, cutaneous allodynia, and spontaneous pain when MN neurons were optically stimulated. Motor functions were also assessed. Optical stimulation of MN neurons decreased the time spent in the light, which was coupled to increased time spent resting in the dark, but not the light. These changes were only significant in female mice. Plantar tactile sensitivity was increased in the ipsilateral paws of both sexes, but contralateral paw data were less clear. There was no significant increase in anxiety-like behavior, spontaneous pain (squint), or changes in gait. These discoveries reveal that MN neurons may contribute to migraine-like sensory hypersensitivity to light and touch.
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http://dx.doi.org/10.1016/j.ynpai.2022.100098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240374PMC
June 2022

CGRP and the Calcitonin Receptor are Co-Expressed in Mouse, Rat and Human Trigeminal Ganglia Neurons.

Front Physiol 2022 10;13:860037. Epub 2022 May 10.

School of Biological Sciences, University of Auckland, Auckland, New Zealand.

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed in the trigeminal ganglia, a key site in craniofacial pain and migraine. CGRP potently activates two receptors: the CGRP receptor and the AMY receptor. These receptors are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with either the calcitonin receptor-like receptor (CLR) to form the CGRP receptor or the calcitonin receptor (CTR) to form the AMY receptor. The expression of the CGRP receptor in trigeminal ganglia has been described in several studies; however, there is comparatively limited data available describing AMY receptor expression and in which cellular subtypes it is found. This research aimed to determine the relative distributions of the AMY receptor subunit, CTR, and CGRP in neurons or glia in rat, mouse and human trigeminal ganglia. Antibodies against CTR, CGRP and neuronal/glial cell markers were applied to trigeminal ganglia sections to investigate their distribution. CTR-like and CGRP-like immunoreactivity were observed in both discrete and overlapping populations of neurons. In rats and mice, 30-40% of trigeminal ganglia neurons displayed CTR-like immunoreactivity in their cell bodies, with approximately 78-80% of these also containing CGRP-like immunoreactivity. Although human cases were more variable, a similar overall pattern of CTR-like immunoreactivity to rodents was observed in the human trigeminal ganglia. CTR and CGRP appeared to be primarily colocalized in small to medium sized neurons, suggesting that colocalization of CTR and CGRP may occur in C-fiber neurons. CGRP-like or CTR-like immunoreactivity were not typically observed in glial cells. Western blotting confirmed that CTR was expressed in the trigeminal ganglia of all three species. These results confirm that CTR is expressed in trigeminal ganglia neurons. The identification of populations of neurons that express both CGRP and CTR suggests that CGRP could act in an autocrine manner through a CTR-based receptor, such as the AMY receptor. Overall, this suggests that a trigeminal ganglia CTR-based receptor may be activated during migraine and could therefore represent a potential target to develop treatments for craniofacial pain and migraine.
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http://dx.doi.org/10.3389/fphys.2022.860037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9128745PMC
May 2022

CGRP Administration Into the Cerebellum Evokes Light Aversion, Tactile Hypersensitivity, and Nociceptive Squint in Mice.

Front Pain Res (Lausanne) 2022 25;3:861598. Epub 2022 Apr 25.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States.

The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous preclinical studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like behaviors in mice, but the sites of action in the brain remain unidentified. The cerebellum has the most CGRP binding sites in the central nervous system and is increasingly recognized as both a sensory and motor integration center. The objective of this study was to test whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. In this study, CGRP was directly injected into the right MN of C57BL/6J mice via a cannula. A battery of tests was done to assess preclinical behaviors that are surrogates of migraine-like symptoms. CGRP caused light aversion measured as decreased time in the light zone even with dim light. The mice also spent more time resting in the dark zone, but not the light, along with decreased rearing and transitions between zones. These behaviors were similar for both sexes. Moreover, significant responses to CGRP were seen in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. Interestingly, CGRP injection caused significant anxiety and spontaneous pain responses only in female mice, and a more robust tactile hypersensitivity in female mice. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP injection in the MN causes light aversion accompanied by increased anxiety, tactile hypersensitivity, and spontaneous pain. A caveat is that we cannot exclude contributions from other cerebellar regions in addition to the MN due to diffusion of the injected peptide. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine-like hypersensitivity.
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http://dx.doi.org/10.3389/fpain.2022.861598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082264PMC
April 2022

Dural Immune Cells, CGRP, and Migraine.

Front Neurol 2022 31;13:874193. Epub 2022 Mar 31.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States.

Migraine is the most common neurological disorder in the world, affecting 12% of the population. Migraine involves the central nervous system, trigeminal nerves and meninges. Recent advances have shown that targeting calcitonin gene-related peptide (CGRP) through either antibodies or small molecule receptor antagonists is effective at reducing episodic and chronic migraine episodes, but these therapeutics are not effective in all patients. This suggests that migraine does not have a singular molecular cause but is likely due to dysregulated physiology of multiple mechanisms. An often-overlooked part of migraine is the potential involvement of the immune system. Clinical studies have shown that migraine patients may have dysregulation in their immune system, with abnormal plasma cytokine levels either during the attack or at baseline. In addition, those who are immunocompromised appear to be at a higher risk of migraine-like disorders. A recent study showed that migraine caused changes to transcription of immune genes in the blood, even following treatment with sumatriptan. The dura mater is densely packed with macrophages, mast and dendritic cells, and they have been found to associate with meningeal blood vessels and trigeminal afferent endings. Recent work in mice shows activation and morphological changes of these cells in rodents following the migraine trigger cortical spreading depression. Importantly, each of these immune cell types can respond directly to CGRP. Since immune cells make up a large portion of the dura, have functional responses to CGRP, and interact with trigeminal afferents, CGRP actions on the dural immune system are likely to play key roles in migraine.
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http://dx.doi.org/10.3389/fneur.2022.874193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009415PMC
March 2022

The voltage-gated Ca2+ channel subunit α2δ-4 regulates locomotor behavior and sensorimotor gating in mice.

PLoS One 2022 30;17(3):e0263197. Epub 2022 Mar 30.

Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, United States of America.

Voltage-gated Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α2δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α2δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α2δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α2δ-4 knockout (KO) mice. α2δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α2δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor coordination in the rotarod assay. α2δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α2δ-4 in sensorimotor gating and motor function and identify α2δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263197PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967030PMC
March 2022

Automated detection of squint as a sensitive assay of sex-dependent calcitonin gene-related peptide and amylin-induced pain in mice.

Pain 2022 08 10;163(8):1511-1519. Epub 2021 Nov 10.

Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.

Abstract: We developed an automated squint assay using both black C57BL/6J and white CD1 mice to measure the interpalpebral fissure area between the upper and lower eyelids as an objective quantification of pain. The automated software detected a squint response to the commonly used nociceptive stimulus formalin in C57BL/6J mice. After this validation, we used the automated assay to detect a dose-dependent squint response to a migraine trigger, the neuropeptide calcitonin gene-related peptide, including a response in female mice at a dose below detection by the manual grimace scale. Finally, we found that the calcitonin gene-related peptide amylin induced squinting behavior in female mice, but not males. These data demonstrate that an automated squint assay can be used as an objective, real-time, continuous-scale measure of pain that provides higher precision and real-time analysis compared with manual grimace assessments.
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http://dx.doi.org/10.1097/j.pain.0000000000002537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085964PMC
August 2022

Investigating Migraine-Like Behavior using Light Aversion in Mice.

J Vis Exp 2021 08 11(174). Epub 2021 Aug 11.

Center for the Prevention and Treatment of Visual Loss, Veterans Administration Health Center, Iowa City, IA; Department of Molecular Physiology and Biophysics, University of Iowa; Department of Neurology, University of Iowa;

Migraine is a complex neurological disorder characterized by headache and sensory abnormalities, such as hypersensitivity to light, observed as photophobia. Whilst it is impossible to confirm that a mouse is experiencing migraine, light aversion can be used as a behavioral surrogate for the migraine symptom of photophobia. To test for light aversion, we utilize the light/dark assay to measure the time mice freely choose to spend in either a light or dark environment. The assay has been refined by introducing two critical modifications: pre-exposures to the chamber prior to running the test procedure and adjustable chamber lighting, permitting the use of a range of light intensities from 55 lux to 27,000 lux. Because the choice to spend more time in the dark is also indicative of anxiety, we also utilize a light-independent anxiety test, the open field assay, to distinguish anxiety from light-aversive behavior. Here, we describe a modified test paradigm for the light/dark and open field assays. The application of these assays is described for intraperitoneal injection of calcitonin gene-related peptide (CGRP) in two mouse strains and for optogenetic brain stimulation studies.
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http://dx.doi.org/10.3791/62839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428768PMC
August 2021

CGRP induces migraine-like symptoms in mice during both the active and inactive phases.

J Headache Pain 2021 Jun 30;22(1):62. Epub 2021 Jun 30.

Department of Molecular Physiology and Biophysics, University of Iowa, 51 Newton Rd, Iowa City, IA, 52242, USA.

Background: Circadian patterns of migraine attacks have been reported by patients but remain understudied. In animal models, circadian phases are generally not taken into consideration. In particular, rodents are nocturnal animals, yet they are most often tested during their inactive phase during the day. This study aims to test the validity of CGRP-induced behavioral changes in mice by comparing responses during the active and inactive phases.

Methods: Male and female mice of the outbred CD1 strain were administered vehicle (PBS) or CGRP (0.1 mg/kg, i.p.) to induce migraine-like symptoms. Animals were tested for activity (homecage movement and voluntary wheel running), light aversive behavior, and spontaneous pain at different times of the day and night.

Results: Peripheral administration of CGRP decreased the activity of mice during the first hour after administration, induced light aversive behavior, and spontaneous pain during that same period of time. Both phenotypes were observed no matter what time of the day or night they were assessed.

Conclusions: A decrease in wheel activity is an additional clinically relevant phenotype observed in this model, which is reminiscent of the reduction in normal physical activity observed in migraine patients. The ability of peripheral CGRP to induce migraine-like symptoms in mice is independent of the phase of the circadian cycle. Therefore, preclinical assessment of migraine-like phenotypes can likely be done during the more convenient inactive phase of mice.
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http://dx.doi.org/10.1186/s10194-021-01277-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243868PMC
June 2021

Hypervigilance, Allostatic Load, and Migraine Prevention: Antibodies to CGRP or Receptor.

Neurol Ther 2021 Dec 2;10(2):469-497. Epub 2021 Jun 2.

Island Neurological Associates, Plainview, NY, USA.

Migraine involves brain hypersensitivity with episodic dysfunction triggered by behavioral or physiological stressors. During an acute migraine attack the trigeminal nerve is activated (peripheral sensitization). This leads to central sensitization with activation of the central pathways including the trigeminal nucleus caudalis, the trigemino-thalamic tract, and the thalamus. In episodic migraine the sensitization process ends with the individual act, but with chronic migraine central sensitization may continue interictally. Increased allostatic load, the consequence of chronic, repeated exposure to stressors, leads to central sensitization, lowering the threshold for future neuronal activation (hypervigilance). Ostensibly innocuous stressors are then sufficient to trigger an attack. Medications that reduce sensitization may help patients who are hypervigilant and help to balance allostatic load. Acute treatments and drugs for migraine prevention have traditionally been used to reduce attack duration and frequency. However, since many patients do not fully respond, an unmet treatment need remains. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in nociception and in the sensitization of peripheral and central neurons of the trigeminovascular system, which is implicated in migraine pathophysiology. Elevated CGRP levels are associated with dysregulated signaling in the trigeminovascular system, leading to maladaptive responses to behavioral or physiological stressors. CGRP may, therefore, play a key role in the underlying pathophysiology of migraine. Increased understanding of the role of CGRP in migraine led to the development of small-molecule antagonists (gepants) and monoclonal antibodies (mAbs) that target either CGRP or the receptor (CGRP-R) to restore homeostasis, reducing the frequency, duration, and severity of attacks. In clinical trials, US Food and Drug Administration-approved anti-CGRP-R/CGRP mAbs were well tolerated and effective as preventive migraine treatments. Here, we explore the role of CGRP in migraine pathophysiology and the use of gepants or mAbs to suppress CGRP-R signaling via inhibition of the CGRP ligand or receptor.
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http://dx.doi.org/10.1007/s40120-021-00250-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571459PMC
December 2021

PACAP Induces Light Aversion in Mice by an Inheritable Mechanism Independent of CGRP.

J Neurosci 2021 05 12;41(21):4697-4715. Epub 2021 Apr 12.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242

The neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about one-third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex linked, although there was a trend for greater responses among male mice. RNA-sequencing analysis of trigeminal ganglia yielded hierarchical clustering of responder and nonresponder mice and revealed a number of candidate genes, including greater expression of the and ion channels and glycoprotein hormones and receptors in a subset of male responder mice. Importantly, an anti-PACAP monoclonal antibody could block PACAP-induced light aversion but not CGRP-induced light aversion. Conversely, an anti-CGRP antibody could not block PACAP-induced light aversion. Thus, we propose that CGRP and PACAP act by independent convergent pathways that cause a migraine-like symptom in mice. The relationship between the neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) in migraine is relevant given that both peptides can induce migraine in people, yet to date only drugs that target CGRP are available. Using an outbred strain of mice, we were able to show that most, but not all, mice respond to PACAP in a preclinical photophobia assay. Our finding that CGRP and PACAP monoclonal antibodies do not cross-inhibit the other peptide indicates that CGRP and PACAP actions are independent and suggests that PACAP-targeted drugs may be effective in patients who do not respond to CGRP-based therapeutics.
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http://dx.doi.org/10.1523/JNEUROSCI.2200-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260237PMC
May 2021

Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients.

Ann Neurol 2021 06 8;89(6):1157-1171. Epub 2021 Apr 8.

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objective: Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood, and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP).

Methods: Thirty-six migraine without aura patients were enrolled in a randomized, double-blind, 2-way, crossover, positive-controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on 2 different experimental days. Furthermore, translational studies in cells and mouse models, and rat, mouse and human tissue samples were conducted.

Results: Thirty patients (88%) developed headache after pramlintide infusion, compared to 33 (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine-like attacks after pramlintide infusion, compared to 19 patients (56%) after CGRP (p = 0.180). The pramlintide-induced migraine-like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide-provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice.

Interpretation: Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. ANN NEUROL 2021;89:1157-1171.
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http://dx.doi.org/10.1002/ana.26072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486152PMC
June 2021

Different forms of traumatic brain injuries cause different tactile hypersensitivity profiles.

Pain 2021 04;162(4):1163-1175

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States.

Abstract: Chronic complications of traumatic brain injury represent one of the greatest financial burdens and sources of suffering in the society today. A substantial number of these patients suffer from posttraumatic headache (PTH), which is typically associated with tactile allodynia. Unfortunately, this phenomenon has been understudied, in large part because of the lack of well-characterized laboratory animal models. We have addressed this gap in the field by characterizing the tactile sensory profile of 2 nonpenetrating models of PTH. We show that multimodal traumatic brain injury, administered by a jet-flow overpressure chamber that delivers a severe compressive impulse accompanied by a variable shock front and acceleration-deceleration insult, produces long-term tactile hypersensitivity and widespread sensitization. These are phenotypes reminiscent of PTH in patients, in both cephalic and extracephalic regions. By contrast, closed head injury induces only transient cephalic tactile hypersensitivity, with no extracephalic consequences. Both models show a more severe phenotype with repetitive daily injury for 3 days, compared with either 1 or 3 successive injuries in a single day, providing new insight into patterns of injury that may place patients at a greater risk of developing PTH. After recovery from transient cephalic tactile hypersensitivity, mice subjected to closed head injury demonstrate persistent hypersensitivity to established migraine triggers, including calcitonin gene-related peptide and sodium nitroprusside, a nitric oxide donor. Our results offer the field new tools for studying PTH and preclinical support for a pathophysiologic role of calcitonin gene-related peptide in this condition.
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http://dx.doi.org/10.1097/j.pain.0000000000002103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008742PMC
April 2021

Vascular actions of peripheral CGRP in migraine-like photophobia in mice.

Cephalalgia 2020 12 18;40(14):1585-1604. Epub 2020 Aug 18.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.

Background: Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice.

Methods: Systemic mean arterial pressure and light aversive behavior were measured after intraperitoneal administration of calcitonin gene-related peptide and vasoactive intestinal peptide in wild-type CD1 mice. The functional significance of vasodilation was tested by co-administration of a vasoconstrictor (phenylephrine, endothelin-1, or caffeine) with calcitonin gene-related peptide to normalize blood pressure during the light aversion assay.

Results: Both calcitonin gene-related peptide and vasoactive intestinal peptide induced light aversion that was associated with their effect on mean arterial pressure. Notably, vasoactive intestinal peptide caused relatively transient vasodilation and light aversion. Calcitonin gene-related peptide-induced light aversion was still observed even with normalized blood pressure. However, two of the agents, endothelin-1 and caffeine, did reduce the magnitude of light aversion.

Conclusion: We propose that perivascular calcitonin gene-related peptide causes light-aversive behavior in mice by both vasomotor and non-vasomotor mechanisms.
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http://dx.doi.org/10.1177/0333102420949173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785273PMC
December 2020

Stimulation of Posterior Thalamic Nuclei Induces Photophobic Behavior in Mice.

Headache 2020 Oct 4;60(9):1961-1981. Epub 2020 Aug 4.

Center for the Prevention and Treatment of Visual Loss, Iowa City, IA, USA.

Objective: A hallmark of migraine is photophobia. In mice, photophobia-like behavior is induced by calcitonin gene-related peptide (CGRP), a neuropeptide known to be a key player in migraine. In this study, we sought to identify sites within the brain from which CGRP could induce photophobia.

Design: We focused on the posterior thalamic region, which contains neurons responsive to both light and dural stimulation and has CGRP binding sites. We probed this area with both optogenetic stimulation and acute CGRP injections in wild-type mice. Since the light/dark assay has historically been used to investigate anxiety-like responses in animals, we measured anxiety in a light-independent open field assay and asked if stimulation of a brain region, the periaqueductal gray, that induces anxiety would yield similar results to posterior thalamic stimulation. The hippocampus was used as an anatomical control to ensure that light-aversive behaviors could not be induced by the stimulation of any brain region.

Results: Optogenetic activation of neuronal cell bodies in the posterior thalamic nuclei elicited light aversion in both bright and dim light without an anxiety-like response in an open field assay. Injection of CGRP into the posterior thalamic region triggered similar light-aversive behavior without anxiety. In contrast to the posterior thalamic nuclei, optogenetic stimulation of dorsal periaqueductal gray cell bodies caused both light aversion and an anxiety-like response, while CGRP injection had no effect. In the dorsal hippocampus, neither optical stimulation nor CGRP injection affected light aversion or open field behaviors.

Conclusion: Stimulation of posterior thalamic nuclei is able to initiate light-aversive signals in mice that may be modulated by CGRP to cause photophobia in migraine.
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http://dx.doi.org/10.1111/head.13917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604789PMC
October 2020

Patients With Vestibular Migraine are More Likely to Have Occipital Headaches than those With Migraine Without Vestibular Symptoms.

Headache 2020 Sep 25;60(8):1581-1591. Epub 2020 Jul 25.

Department of Neurology, University of Iowa, Iowa City, IA, USA.

Objective: To determine whether patients with vestibular migraine are more likely to suffer from an occipital headache than patients with migraine without vestibular symptoms.

Background: Vestibular migraine is an underdiagnosed disorder in which migraine is associated with vestibular symptoms. Anatomical evidence and symptomatology hint at the involvement of brain structures in the posterior fossa (back of the head location). We hypothesized that vestibular migraine patients are more likely than migraineurs without vestibular symptoms to experience headaches located in the back of the head, that is, occipital headaches.

Methods: A retrospective cross-sectional study was conducted at the University of Iowa Hospital and Clinics. Chart analysis of 169 patients was performed. The primary outcome was the location of the headache in vestibular migraine patients and migraineurs without vestibular symptoms. The secondary outcomes included the association of vestibular migraine with gender, age at onset of headache, age at onset of vestibular symptoms (such as vertigo, head motion-induced dizziness), aura, motion sickness, other associated symptoms, family history of headaches, and family history of motion sickness.

Results: In vestibular migraine group, 45/103 (44%) had occipital location for their headaches vs 12/66 (18%) in migraine patients without vestibular symptoms, for an odd's ratio of 3.5 (95% CI = 1.7-7.2, P < .001). Additionally, the age at onset of headache was greater in the vestibular migraine group (28 ± 12 vs 18 ± 9 years, P < .001) and motion sickness was more common (41/98 (42%) in the vestibular migraine group, 1/64 (2%) in the migraine without vestibular symptoms group, P < .001).

Conclusions: This study suggests that patients with vestibular migraine are more likely to have occipital headaches than patients with migraine without vestibular symptoms. Our data support the initiation of a prospective study to determine whether a patient presenting with occipital headaches, with late onset of age of headache, and with a history of motion sickness is at an increased risk for the possible development of vestibular migraine.
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http://dx.doi.org/10.1111/head.13898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771256PMC
September 2020

A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine.

J Pharm Pharmacol 2020 Oct 25;72(10):1352-1360. Epub 2020 Jun 25.

School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.

Objectives: To investigate the formulation of the peptide-based antagonist ( Pro, Phe)CGRP , of the human calcitonin gene-related peptide (CGRP) receptor as a potential nasally delivered migraine treatment.

Methods: Peptide sequences were prepared using automated methods and purified by preparative HPLC. Their structure and stability were determined by LC-MS. Antagonist potency was assessed by measuring CGRP-stimulated cAMP accumulation in SK-N-MC, cells and in CHO cells overexpressing the human CGRP receptor. In vivo activity was tested in plasma protein extravasation (PPE) studies using Evans blue dye accumulation. Peptide-containing chitosan microparticles were prepared by spray drying.

Key Findings: ( Pro, Phe)CGRP exhibited a 10-fold increased affinity compared to αCGRP . Administration of ( Pro, Phe)CGRP to mice led to a significant decrease in CGRP-induced PPE confirming antagonistic properties in vivo. There was no degradation of ( Pro, Phe)CGRP and no loss of antagonist potency during formulation and release from chitosan microparticles.

Conclusions: ( Pro, Phe)CGRP is a potent CGRP receptor antagonist both in vitro and in vivo, and it can be formulated as a dry powder with no loss of activity indicating its potential as a nasally formulated anti-migraine medicine.
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http://dx.doi.org/10.1111/jphp.13317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486274PMC
October 2020

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators.

J Neural Transm (Vienna) 2020 04 22;127(4):431-444. Epub 2020 Feb 22.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, 52242, USA.

The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons are surrounded by satellite glial cells and the axons are wrapped by myelinating and non-myelinating Schwann cells. Trigeminal neurons express various neuropeptides, most notably, calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP). Two types of CGRP receptors are expressed in neurons and satellite glia. A variety of other signal molecules like ATP, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion neurons and signal to neighboring neurons or satellite glial cells, which can signal back to neurons with same or other mediators. This potential cross-talk of signals involves intracellular mechanisms, including gene expression, that can modulate mediators of sensory information, such as neuropeptides, receptors, and neurotrophic factors. From the ganglia cell bodies, which are outside the blood-brain barrier, the mediators are further distributed to peripheral sites and/or to the spinal trigeminal nucleus in the brainstem, where they can affect neural transmission. A major question is how the sensory neurons in the trigeminal ganglion differ from those in the dorsal root ganglion. Despite their functional overlap, there are distinct differences in their ontogeny, gene expression, signaling pathways, and responses to anti-migraine drugs. Consequently, drugs that modulate cross-talk in the trigeminal ganglion can modulate both peripheral and central sensitization, which may potentially be distinct from sensitization mediated in the dorsal root ganglion.
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http://dx.doi.org/10.1007/s00702-020-02161-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148261PMC
April 2020

Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting.

Expert Opin Ther Targets 2020 02 13;24(2):91-100. Epub 2020 Feb 13.

Department of Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.

: The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a critical player in migraine pathophysiology. Excitement has grown regarding CGRP because of the development and clinical testing of drugs targeting CGRP or its receptor. While these drugs alleviate migraine symptoms in half of the patients, the remaining unresponsive half of this population creates an impetus to address unanswered questions that exist in this field.: We describe the role of CGRP in migraine pathophysiology and CGRP-targeted therapeutics currently under development and in use. We also discuss how a second CGRP receptor may provide a new therapeutic target.: CGRP-targeting drugs have shown a remarkable safety profile. We speculate that this may reflect the redundancy of peptides within the CGRP family and a second CGRP receptor that may compensate for reduced CGRP activity. Furthermore, we propose that an inherent safety feature of peptide-blocking antibodies is attributed to the fundamental nature of peptide release, which occurs as a large bolus in short bursts of volume transmission. These facts support the development of more refined CGRP therapeutic drugs, as well as drugs that target other neuropeptides. We believe that the future of migraine research is bright with exciting advances on the horizon.
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http://dx.doi.org/10.1080/14728222.2020.1724285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050542PMC
February 2020

CGRP-based Migraine Therapeutics: How Might They Work, Why So Safe, and What Next?

Authors:
Andrew F Russo

ACS Pharmacol Transl Sci 2019 Feb 5;2(1):2-8. Epub 2018 Nov 5.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, 52242.

Migraine is a debilitating neurological condition that involves the neuropeptide calcitonin gene-related peptide (CGRP). An exciting development is the recent FDA approval of the first in an emerging class of CGRP-targeted drugs designed to prevent migraine. Yet despite this efficacy, there are some fundamental unanswered questions, such as and CGRP works in migraine. Preclinical data suggest that CGRP acts via both peripheral and central mechanisms. The relevance of peripheral sites is highlighted by the clinical efficacy of CGRP-blocking antibodies, even though they do not appreciably cross the blood-brain barrier. The most likely sites of action are within the dura and trigeminal ganglia. Furthermore, it would be foolish to ignore perivascular actions in the dura since CGRP is the most potent vasodilatory peptide. Ultimately, the consequence of blocking CGRP or its receptor is reduced peripheral neural sensitization. Underlying their efficacy is the question of the antibodies have such an excellent safety profile so far. This may be due to the presence of a second CGRP receptor and vesicular release of a large bolus of peptides. Finally, despite the promise of these drugs, there are unmet gaps because they do not work for all patients; so ? We can expect advances on several fronts, including CGRP receptor structures that may help development of centrally-acting antagonists, combinatorial treatments that integrate other therapies, and development of drugs that target other neuropeptides. This is truly an exciting time for CGRP and the migraine field with many more discoveries on the horizon.
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http://dx.doi.org/10.1021/acsptsci.8b00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761833PMC
February 2019

Behavioral and cognitive animal models in headache research.

J Headache Pain 2019 Jan 31;20(1):11. Epub 2019 Jan 31.

Department of Neurology and Algology, Gazi University Faculty of Medicine, Besevler, 06510, Ankara, Turkey.

Animal models have provided a growing body of information about the pathophysiology of headaches and novel therapeutic targets. In recent years, experiments in awake animals have gained attention as more relevant headache models. Pain can be assessed in animals using behavioral alterations, which includes sensory-discriminative, affective-emotional and cognitive aspects. Spontaneous behavioral alterations such as increased grooming, freezing, eye blinking, wet dog shake and head shake and decreased locomotion, rearing, food or water consumption observed during pain episodes are oftentimes easy to translate into clinical outcomes, but are giving little information about the localization and modality of the pain. Evoked pain response such as tactile and thermal hypersensitivity measures are less translatable but gives more insight into mechanisms of action. Mechanical allodynia is usually assessed with von Frey monofilaments and dynamic aesthesiometer, and thermal allodynia can be evaluated with acetone evaporation test and Hargreaves' test in animal models. Anxiety and depression are the most frequent comorbid diseases in headache disorders. Anxiety-like behaviors are evaluated with the open-field, elevated plus-maze or light/dark box tests. Interpretation of the latter test is challenging in migraine models, as presence of photophobia or photosensitivity can also be measured in light/dark boxes. Depressive behavior is assessed with the forced-swim or tail suspension tests. The majority of headache patients complain of cognitive symptoms and migraine is associated with poor cognitive performance in clinic-based studies. Cluster headache and tension type headache patients also exhibit a reversible cognitive dysfunction during the headache attacks. However, only a limited number of animal studies have investigated cognitive aspects of headache disorders, which remains a relatively unexplored aspect of these pathologies. Thus, the headache field has an excellent and growing selection of model systems that are likely to yield exciting advances in the future.
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http://dx.doi.org/10.1186/s10194-019-0963-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734244PMC
January 2019

CGRP in Animal Models of Migraine.

Handb Exp Pharmacol 2019 ;255:85-107

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.

With the approval of calcitonin gene-related peptide (CGRP) and CGRP receptor monoclonal antibodies by the Federal Drug Administration, a new era in the treatment of migraine patients is beginning. However, there are still many unknowns in terms of CGRP mechanisms of action that need to be elucidated to allow new advances in migraine therapies. CGRP has been studied both clinically and preclinically since its discovery. Here we review some of the preclinical data regarding CGRP in animal models of migraine.
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http://dx.doi.org/10.1007/164_2018_187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008000PMC
September 2019

Vascular Contributions to Migraine: Time to Revisit?

Front Cell Neurosci 2018 3;12:233. Epub 2018 Aug 3.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States.

Migraine is one of the most prevalent and disabling neurovascular disorders worldwide. However, despite the increase in awareness and research, the understanding of migraine pathophysiology and treatment options remain limited. For centuries, migraine was considered to be a vascular disorder. In fact, the throbbing, pulsating quality of the headache is thought to be caused by mechanical changes in vessels. Moreover, the most successful migraine treatments act on the vasculature and induction of migraine can be accomplished with vasoactive agents. However, over the past 20 years, the emphasis has shifted to the neural imbalances associated with migraine, and vascular changes have generally been viewed as an epiphenomenon that is neither sufficient nor necessary to induce migraine. With the clinical success of peripherally-acting antibodies that target calcitonin gene-related peptide (CGRP) and its receptor for preventing migraine, this neurocentric view warrants a critical re-evaluation. This review will highlight the likely importance of the vasculature in migraine.
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http://dx.doi.org/10.3389/fncel.2018.00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088188PMC
August 2018

Peripherally administered calcitonin gene-related peptide induces spontaneous pain in mice: implications for migraine.

Pain 2018 Nov;159(11):2306-2317

Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IA, United States.

Migraine is the third most common disease in the world (behind dental caries and tension-type headache) with an estimated global prevalence of 15%, yet its etiology remains poorly understood. Recent clinical trials have heralded the potential of therapeutic antibodies that block the actions of the neuropeptide calcitonin gene-related peptide (CGRP) or its receptor to prevent migraine. Calcitonin gene-related peptide is believed to contribute to trigeminal nerve hypersensitivity and photosensitivity in migraine, but a direct role in pain associated with migraine has not been established. In this study, we report that peripherally administered CGRP can act in a light-independent manner to produce spontaneous pain in mice that is manifested as a facial grimace. As an objective validation of the orbital tightening action unit of the grimace response, we developed a squint assay using a video-based measurement of the eyelid fissure, which confirmed a significant squint response after CGRP injection, both in complete darkness and very bright light. These indicators of discomfort were completely blocked by preadministration of a monoclonal anti-CGRP-blocking antibody. However, the nonsteroidal anti-inflammatory drug meloxicam failed to block the effect of CGRP. Interestingly, an apparent sex-specific response to treatment was observed with the antimigraine drug sumatriptan partially blocking the CGRP response in male, but not female mice. These results demonstrate that CGRP can induce spontaneous pain, even in the absence of light, and that the squint response provides an objective biomarker for CGRP-induced pain that is translatable to humans.
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http://dx.doi.org/10.1097/j.pain.0000000000001337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193822PMC
November 2018

Current understanding of trigeminal ganglion structure and function in headache.

Cephalalgia 2019 11 10;39(13):1661-1674. Epub 2018 Jul 10.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.

Introduction: The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its cellular components. Being mainly responsible for the sensory innervation of the anterior regions of the head, it is a major target for headache research. One intriguing question is if the trigeminal ganglion is merely a transition site for sensory information from the periphery to the central nervous system, or if intracellular modulatory mechanisms and intercellular signaling are capable of controlling sensory information relevant for the pathophysiology of headaches.

Methods: An online search based on PubMed was made using the keyword "trigeminal ganglion" in combination with "anatomy", "headache", "migraine", "neuropeptides", "receptors" and "signaling". From the relevant literature, further references were selected in view of their relevance for headache mechanisms. The essential information was organized based on location and cell types of the trigeminal ganglion, neuropeptides, receptors for signaling molecules, signaling mechanisms, and their possible relevance for headache generation.

Results: The trigeminal ganglion consists of clusters of sensory neurons and their peripheral and central axon processes, which are arranged according to the three trigeminal partitions V1-V3. The neurons are surrounded by satellite glial cells, the axons by Schwann cells. In addition, macrophage-like cells can be found in the trigeminal ganglion. Neurons express various neuropeptides, among which calcitonin gene-related peptide is the most prominent in terms of its prevalence and its role in primary headaches. The classical calcitonin gene-related peptide receptors are expressed in non-calcitonin gene-related peptide neurons and satellite glial cells, although the possibility of a second calcitonin gene-related peptide receptor in calcitonin gene-related peptide neurons remains to be investigated. A variety of other signal molecules like adenosine triphosphate, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion cells and may act at receptors on adjacent neurons or satellite glial cells.

Conclusions: The trigeminal ganglion may act as an integrative organ. The morphological and functional arrangement of trigeminal ganglion cells suggests that intercellular and possibly also autocrine signaling mechanisms interact with intracellular mechanisms, including gene expression, to modulate sensory information. Receptors and neurotrophic factors delivered to the periphery or the trigeminal brainstem can contribute to peripheral and central sensitization, as in the case of primary headaches. The trigeminal ganglion as a target of drug action outside the blood-brain barrier should therefore be taken into account.
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http://dx.doi.org/10.1177/0333102418786261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007999PMC
November 2019

Cortical spreading depression as a site of origin for migraine: Role of CGRP.

Cephalalgia 2019 03 25;39(3):428-434. Epub 2018 Apr 25.

4 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.

Premise: Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood.

Problem: One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression.

Conclusion: This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.
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http://dx.doi.org/10.1177/0333102418774299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007998PMC
March 2019

Increased receptor activity-modifying protein 1 in the nervous system is sufficient to protect against autonomic dysregulation and hypertension.

J Cereb Blood Flow Metab 2019 04 3;39(4):690-703. Epub 2018 Jan 3.

1 Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.

Calcitonin gene-related peptide (CGRP) can cause migraines, yet it is also a potent vasodilator that protects against hypertension. Given the emerging role of CGRP-targeted antibodies for migraine prevention, an important question is whether the protective actions of CGRP are mediated by vascular or neural CGRP receptors. To address this, we have characterized the cardiovascular phenotype of transgenic nestin/hRAMP1 mice that have selective elevation of a CGRP receptor subunit in the nervous system, human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice had relatively little hRAMP1 RNA in blood vessels and intravenous injection of CGRP caused a similar blood pressure decrease in transgenic and control mice. At baseline, nestin/hRAMP1 mice exhibited similar mean arterial pressure, heart rate, baroreflex sensitivity, and sympathetic vasomotor tone as control mice. We previously reported that expression of hRAMP1 in all tissues favorably improved autonomic regulation and attenuated hypertension induced by angiotensin II (Ang II). Similarly, in nestin/hRAMP1 mice, hypertension caused by Ang II or phenylephrine was greatly attenuated, and associated autonomic dysregulation and increased sympathetic vasomotor tone were diminished or abolished. We conclude that increased expression of neuronal CGRP receptors is sufficient to induce a protective change in cardiovascular autonomic regulation with implications for migraine therapy.
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http://dx.doi.org/10.1177/0271678X17751352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446426PMC
April 2019

Overview of Neuropeptides: Awakening the Senses?

Authors:
Andrew F Russo

Headache 2017 May;57 Suppl 2:37-46

Department of Molecular Physiology and Biophysics, Department of Neurology, University of Iowa, Iowa City, IA, 52242, USA.

Humans have a diverse collection of neuropeptides that can influence a multitude of activities. There are now over 100 known neuropeptides and probably many more yet to be identified from the over 1000 predicted peptides encoded in the genome. While diverse, peptides generally share three common characteristics: (1) post-translational processing and release from vesicles, (2) activation of cell-surface receptors over a relatively large distance, and (3) modulation of target cells that are often in the brain and periphery. Within the brain, neuropeptides can modulate the activity of co-released neurotransmitters to either increase or decrease the strength of synaptic signaling. Within the periphery, neuropeptides can function similar to peptide hormones and modulate nearly all bodily functions. Given the clear involvement of the neuropeptide CGRP in migraine and the emerging evidence for other peptides, it seems likely that neuropeptides may help "awaken" the senses and contribute to the heightened sensory state of migraine.
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http://dx.doi.org/10.1111/head.13084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424629PMC
May 2017

CGRP receptor activity in mice with global expression of human receptor activity modifying protein 1.

Br J Pharmacol 2017 06 22;174(12):1826-1840. Epub 2017 Apr 22.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.

Background And Purpose: CGRP is a potent vasodilator and nociceptive neuropeptide linked to migraine. CGRP receptors are heterodimers of receptor activity modifying protein 1 (RAMP1) and either calcitonin receptor-like receptor (CLR; forms canonical CGRP receptor) or calcitonin receptor (CT receptor; forms AMY receptor). The goal of this study was to test whether transgenic mice globally expressing human RAMP1 have increased CGRP receptor activity and whether the receptors are sensitive to human selective antagonist telcagepant.

Experimental Approach: cAMP production was measured in primary cultures of aortic smooth muscle and trigeminal ganglia neurons from global hRAMP1 mice and non-transgenic littermates. Functional activity and inhibition were compared with clonal cell lines expressing combinations of CLR or CT receptors with RAMP1.

Key Results: Cultured smooth muscle from global hRAMP1 mice had a 10-fold greater CGRP-induced cAMP maximal response (Rmax) than non-transgenic littermates, with similar EC s. In contrast, cultured trigeminal ganglia from global hRAMP1 mice had a 40-fold leftward shift of the EC , with similar Rmax values as littermates. In both hRAMP1 cultures, telcagepant blocked CGRP-induced cAMP production, but was not effective in non-transgenic cultures. IC values were closer to those observed for CT receptor/hRAMP1 than CLR/hRAMP1 in clonal cell lines.

Conclusions And Implications: Overexpression of hRAMP1 increases CGRP signalling by changing the maximal response or ligand sensitivity, depending on tissue type. Furthermore, telcagepant inhibited transgenic hRAMP1 CGRP receptors, but the degree of inhibition suggests that the transgenic mice are only partially humanized or both canonical CGRP and AMY receptors are functional in trigeminal ganglia neurons and vascular smooth muscle.
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http://dx.doi.org/10.1111/bph.13783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446571PMC
June 2017
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