scholarly journals Evaluation of LY573144 (lasmiditan) in a preclinical model of medication overuse headache

Cephalalgia ◽  
2020 ◽  
Vol 40 (9) ◽  
pp. 903-912 ◽  
Author(s):  
Jill C Rau ◽  
Edita Navratilova ◽  
Janice Oyarzo ◽  
Kirk W Johnson ◽  
Sheena K Aurora ◽  
...  
Keyword(s):  
Rat Model ◽  
Acute Treatment ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Light Stress ◽  
Preclinical Model ◽  
Sprague Dawley ◽  
Drug Induced ◽  
No Donor ◽  
Cutaneous Allodynia

Background Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model. Methods Sprague Dawley rats were administered six doses of lasmiditan (10 mg/kg), sumatriptan (10 mg/kg), or sterile water orally over 2 weeks and cutaneous allodynia was evaluated regularly in the periorbital and hindpaw regions using von Frey filaments. Testing continued until mechanosensitivity returned to baseline levels. Rats were then submitted to bright light stress (BLS) or nitric oxide (NO) donor administration and were again evaluated for cutaneous allodynia in the periorbital and hindpaw regions hourly for 5 hours. Results Both lasmiditan and sumatriptan exhibited comparable levels of drug-induced cutaneous allodynia in both the periorbital and hindpaw regions, which resolved after cessation of drug administration. Both lasmiditan and sumatriptan pre-treatment resulted in cutaneous allodynia that was evoked by either BLS or NO donor. Conclusions In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms.

scholarly journals Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache

Cephalalgia ◽  
2020 ◽  
Vol 40 (9) ◽  
pp. 892-902 ◽  
Author(s):  
Edita Navratilova ◽  
Sasan Behravesh ◽  
Janice Oyarzo ◽  
David W Dodick ◽  
Pradeep Banerjee ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Treatment ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Light Stress ◽  
Bright Light ◽  
Nitric Oxide Donor ◽  
Preclinical Model ◽  
Cutaneous Allodynia ◽  
Oral Doses

Background Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats. Methods A “two-hit” priming model of medication overuse headache was used. Female Sprague-Dawley rats received six oral doses of sumatriptan 10 mg/kg over 2 weeks to induce latent sensitization (i.e. “priming”). Cutaneous allodynia was measured periodically over 20 days in the periorbital and hindpaw regions using von Frey filaments. The rats were then subjected to a 1-hour bright light stress challenge on two consecutive days. At the start of the second bright light stress exposure, oral sumatriptan 10 mg/kg, oral ubrogepant 25, 50, or 100 mg/kg, or vehicle was administered; thereafter, cephalic and hindpaw sensory thresholds were monitored hourly over 5 hours to determine the efficacy of ubrogepant in reversing bright light stress-induced cutaneous allodynia. A dose of ubrogepant effective in the medication overuse headache model (100 mg/kg) was then selected to determine if repeated administration would produce latent sensitization. Rats were administered six oral doses of ubrogepant 100 mg/kg, sumatriptan 10 mg/kg (positive control), or vehicle over 2 weeks, and cutaneous allodynia was evaluated regularly. Testing continued until mechanosensitivity returned to baseline levels. Rats were then challenged with bright light stress on days 20 and 21, and periorbital and hindpaw cutaneous allodynia was measured. On days 28 to 32, the same groups received a nitric oxide donor (sodium nitroprusside 3 mg/kg, i.p.), and cutaneous allodynia was assessed hourly over 5 hours. Results Sumatriptan elicited cutaneous allodynia in both cephalic and hindpaw regions; cutaneous allodynia resolved to baseline levels after cessation of drug administration (14 days). Sumatriptan priming resulted in generalized and delayed cutaneous allodynia, evoked by either bright light stress (day 21) or nitric oxide donor (day 28). Ubrogepant dose-dependently blocked both stress- and nitric oxide donor-induced cephalic and hindpaw allodynia in the sumatriptan-induced medication overuse headache model with a 50% effective dose of ∼50 mg/kg. Unlike sumatriptan, ubrogepant 100 mg/kg in repeated effective doses did not produce cutaneous allodynia or latent sensitization. Conclusions Both ubrogepant and sumatriptan demonstrated efficacy as acute medications for stress- and nitric oxide donor-evoked cephalic allodynia in a preclinical model of medication overuse headache, consistent with their clinical efficacy in the acute treatment of migraine. However, in contrast to sumatriptan, repeated treatment with ubrogepant did not induce cutaneous allodynia or latent sensitization. These studies suggest ubrogepant may offer an effective acute treatment of migraine without risk of medication overuse headache. Trial Registration Number: Not applicable

scholarly journals Cannabinoids induce latent sensitization in a preclinical model of medication overuse headache

Cephalalgia ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 68-78 ◽  
Author(s):  
Caroline M Kopruszinski ◽  
Edita Navratilova ◽  
Barbora Vagnerova ◽  
Juliana Swiokla ◽  
Amol Patwardhan ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Light Stress ◽  
Drug Discontinuation ◽  
Preclinical Model ◽  
Tail Flick ◽  
Sensory Thresholds ◽  
Tail Flick Test ◽  
Receptor Agonists

Aim Evaluation of cannabinoid receptor agonists in a preclinical model of medication overuse headache. Methods Female Sprague Dawley rats received graded intraperitoneal doses of WIN55,212-2 or Δ-9-tetrahydrocannabinol (Δ-9-THC). Antinociception (tail-flick test), catalepsy and hypomotility (open field test) and impairment of motor function (rotarod test) were assessed to establish effective dosing. Rats were then treated twice daily with equianalgesic doses of WIN55,212-2 or Δ-9-THC, or vehicle, for 7 days and cutaneous tactile sensory thresholds were evaluated during and three weeks following drug discontinuation. Rats then received a one-hour period of bright light stress (BLS) on two consecutive days and tactile sensory thresholds were re-assessed. Results WIN55,212-2 and Δ-9-THC produced antinociception as well as hypomotility, catalepsy and motor impairment. Repeated administration of WIN55,212-2 and Δ-9-THC induced generalized periorbital and hindpaw allodynia that resolved within 3 weeks after discontinuation of drug. Two episodes of BLS produced delayed and long-lasting periorbital and hindpaw allodynia selectively in rats previously treated with WIN55,212-2, and Δ-9-THC. Interpretation Cannabinoid receptor agonists including Δ-9-THC produce a state of latent sensitization characterized by increased sensitivity to stress, a presumed migraine trigger. Overuse of cannabinoids including cannabis may increase the risk of medication overuse headache in vulnerable individuals.

Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents

Cephalalgia ◽  
2016 ◽  
Vol 37 (6) ◽  
pp. 560-570 ◽  
Author(s):  
Caroline Machado Kopruszinski ◽  
Jennifer Yanhua Xie ◽  
Nathan Mackenzie Eyde ◽  
Bethany Remeniuk ◽  
Sarah Walter ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Light Stress ◽  
Calcitonin Gene Related Peptide ◽  
Nitric Oxide Donor ◽  
Acute Migraine ◽  
No Donor ◽  
Related Peptide ◽  
Calcitonin Gene

Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.

A prolactin-dependent sexually dimorphic mechanism of migraine chronification

Cephalalgia ◽  
2021 ◽  
pp. 033310242110398
Author(s):  
Daigo Ikegami ◽  
Edita Navratilova ◽  
Xu Yue ◽  
Aubin Moutal ◽  
Caroline M Kopruszinski ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Nasal Delivery ◽  
Nasal Administration ◽  
Dopamine Receptor Agonist ◽  
Sexually Dimorphic ◽  
Down Regulation ◽  
Female Mice ◽  
Cutaneous Allodynia

Objective Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms. Background The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective. Methods Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms. Results PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females. Interpretation We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.

scholarly journals Validation of potential candidate biomarkers of drug-induced nephrotoxicity and allodynia in medication-overuse headache

2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Elisa Bellei ◽  
Emanuela Monari ◽  
Stefania Bergamini ◽  
Aurora Cuoghi ◽  
Aldo Tomasi ◽  
...  
Keyword(s):  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Potential Candidate ◽  
Drug Induced

scholarly journals Discovery by a proteomic approach of possible early biomarkers of drug-induced nephrotoxicity in medication-overuse headache

2013 ◽  
Vol 14 (1) ◽  
Author(s):  
Elisa Bellei ◽  
Emanuela Monari ◽  
Aurora Cuoghi ◽  
Stefania Bergamini ◽  
Simona Guerzoni ◽  
...  
Keyword(s):  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Drug Induced ◽  
Early Biomarkers ◽  
Proteomic Approach

scholarly journals Altered activity in the nucleus raphe magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Prangtip Potewiratnanond ◽  
Supang Maneesri le Grand ◽  
Anan Srikiatkhachorn ◽  
Weera Supronsinchai
Keyword(s):  
Rat Model ◽  
Chronic Exposure ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Neuronal Firing ◽  
Control Group ◽  
Nucleus Raphe Magnus ◽  
Cortical Hyperexcitability ◽  
Trigeminal Nociception ◽  
Raphe Magnus

Abstract Background The pathogenesis of medication overuse headache (MOH) involves hyperexcitability of cortical and trigeminal neurons. Derangement of the brainstem modulating system, especially raphe nuclei may contribute to this hyperexcitability. The present study aimed to investigate the involvement of the nucleus raphe magnus (NRM) in the development of cortical and trigeminal hyperexcitability in a rat model of MOH. Results Chronic treatment with acetaminophen increased the frequency of cortical spreading depression (CSD) and the number of c-Fos-immunoreactive (Fos-IR) neurons in the trigeminal nucleus caudalis (TNC). In the control group, muscimol microinjected into the NRM increased significantly the frequency of CSD-evoked direct current shift and Fos-IR neurons in the TNC. This facilitating effect was not found in rats with chronic acetaminophen exposure. In a model of migraine induced by intravenous systemic infusion of nitroglycerin (NTG), rats with chronic exposure to acetaminophen exhibited significantly more frequent neuronal firing in the TNC and greater Fos-IR than those without the acetaminophen treatment. Muscimol microinjection increased neuronal firing in the TNC in control rats, but not in acetaminophen-treated rats. The number of Fos-IR cells in TNC was not changed significantly. Conclusion Chronic exposure to acetaminophen alters the function of the NRM contributing to cortical hyperexcitability and facilitating trigeminal nociception.

Drug-induced changes in cortical inhibition in medication overuse headache

Cephalalgia ◽  
2011 ◽  
Vol 31 (12) ◽  
pp. 1282-1290 ◽  
Author(s):  
Antonio Currà ◽  
Gianluca Coppola ◽  
Manuela Gorini ◽  
Elisa Porretta ◽  
Martina Bracaglia ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Primary Motor Cortex ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Silent Period ◽  
Cortical Inhibition ◽  
Drug Induced ◽  
Normal Limits ◽  
Inhibitory Mechanisms ◽  
Episodic Migraineurs

Background: We investigated whether chronic headache related to medication overuse (MOH) is associated with changes in brain mechanisms regulating inhibitory cortical responses compared with healthy volunteers and episodic migraineurs recorded between attacks, and whether these changes differ according to the drug overused. Subjects and Methods: We studied 40 MOH patients whose symptoms were related to triptans alone, non-steroidal anti-inflammatory drugs (NSAIDs) or both medications combined, 12 migraineurs and 13 healthy volunteers. We used high-intensity transcranial magnetic stimulation over the primary motor cortex to assess the silent period from contracted perioral muscles. Results: In MOH patients the cortical silent period differed according to the type of headache medication overused: in patients overusing triptans alone it was shorter than in healthy volunteers (44.7 ± 14.2 vs. 108.1 ± 30.1 ms), but similar to that reported in migraineurs (59.9 ± 30.4 ms), whereas in patients overusing NSAIDs alone or triptans and NSAIDs combined duration of silent period was within normal limits (80.6 ± 46.4 and 103.8 ± 47.2 ms). Conclusions: Compared with episodic migraineurs, MOH patients overusing triptans have no significant change in cortical inhibition, whereas those overusing NSAIDs have an increase in cortical inhibitory mechanisms. We attribute these changes to medication-induced neural adaptation promoted by changes in central serotonin neurotransmission.

scholarly journals The Effect of Sertoli Cells on Xenotransplantation and Allotransplantation of Ventral Mesencephalic Tissue in a Rat Model of Parkinson’s Disease

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1420
Author(s):  
Yun-Ting Jhao ◽  
Chuang-Hsin Chiu ◽  
Chien-Fu F. Chen ◽  
Ta-Kai Chou ◽  
Yi-Wen Lin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Sertoli Cells ◽  
Dopaminergic Neurons ◽  
Sprague Dawley ◽  
Drug Induced ◽  
In Vivo Evaluation ◽  
Ventral Mesencephalic

Intra-striatal transplantation of fetal ventral mesencephalic (VM) tissue has a therapeutic effect on patients with Parkinson’s disease (PD). Sertoli cells (SCs) possess immune-modulatory properties that benefit transplantation. We hypothesized that co-graft of SCs with VM tissue can attenuate rejection. Hemi-parkinsonian rats were generated by injecting 6-hydroxydopamine into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats or pigs (rVM or pVM), with/without a co-graft of SCs (rVM+SCs or pVM+SCs). Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. Immunohistochemistry (IHC) examination was used to determine the survival of the grafted dopaminergic neurons in the striatum and to investigate immune-modulatory effects of SCs. The results showed that the rVM+SCs and pVM+SCs groups had significantly improved drug-induced rotational behavior compared with the VM alone groups. PET revealed a significant increase in specific uptake ratios (SURs) of [18F] DOPA and [18F] FE-PE2I in the grafted striatum of the rVM+SCs and pVM+SCs groups as compared to that of the rVM and pVM groups. SC and VM tissue co-graft led to better dopaminergic (DA) cell survival. The co-grafted groups exhibited lower populations of T-cells and activated microglia compared to the groups without SCs. Our results suggest that co-graft of SCs benefit both xeno- and allo-transplantation of VM tissue in a PD rat model. Use of SCs enhanced the survival of the grafted dopaminergic neurons and improved functional recovery. The enhancement may in part be attributable to the immune-modulatory properties of SCs. In addition, [18F]DOPA and [18F]FE-PE2I coupled with PET may provide a feasible method for in vivo evaluation of the functional integrity of the grafted DA cell in parkinsonian rats.

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