Background & Aims
The National Institutes of Health Helping to End Addiction Long-termSM Initiative, or NIH HEAL Initiative, Preclinical Screening Platform for Pain (PSPP) program aims to accelerate the discovery and development of novel non-opioid, non-addictive pain therapeutics. The PSPP program accepts small molecules, biologics, natural products and devices from industry, academia or government asset owners. In collaboration with PsychoGenics, Inc., assets are evaluated to determine in vitro functional properties, pharmacokinetics, side effect profile, abuse liability, and efficacy in preclinical pain models. Efforts in the PSPP program are also focused on the characterization and optimization of disease-specific models to provide support for specific pain indications. Here, we describe one such effort to characterize the pharmacology of rat models of vascular headache and trigeminal sensitization involving administration of isosorbide dinitrate or dural infusion of inflammatory soup (IS).
Methods
Adult male and female Sprague Dawley rats (n=10, each sex) were used in these studies. For the model of vascular headache, the nitric oxide donor isosorbide dinitrate (ISDN; 10 mg/kg) was injected intraperitoneal (i.p.). For the model of trigeminal sensitization, rats received single or multiple infusions of inflammatory soup (IS; 2 mM serotonin, histamine, bradykinin, 0.2 mM PGE2) onto the dura under acute isoflurane anesthesia. Facial allodynia was measured by applying calibrated von Frey filaments to the periorbital region of the face and determining facial sensitivity thresholds (facial swipe/head withdrawal). Pharmacology was examined by evaluating the effects of pretreatment with the reference compounds morphine sulfate (6 mg/kg), naproxen (30 mg/kg), sumatriptan (1 mg/kg), olcegepant (1 mg/kg), SNC80 (30 mg/kg), and dipraglurant (50 mg/kg). Data were analyzed using two-way repeated measures ANOVA with Bonferroni’s or Dunnett’s post hoc test where appropriate.
Results
In the models of vascular headache and trigeminal sensitization, administration of ISDN or IS produced a transient facial allodynia which persisted for a longer duration in female rats in comparison to male rats. Multiple infusions of IS onto the dura once per day for 5 consecutive days resulted in a persistent facial allodynia which was robust and continued following the discontinuation of the IS infusions. Reference analgesic compounds were evaluated by pretreating rats prior to induction of vascular headache or trigeminal sensitization. Administration of the mu opioid receptor agonist morphine sulfate or delta opioid receptor agonist SNC80 completely prevented the development of facial allodynia. Pretreatment with the 5-HT1B/1D receptor agonist sumatriptan or CGRP receptor antagonist olcegepant partially prevented the development facial allodynia, while pretreatment with the NSAID naproxen or mGluR5 negative allosteric modulator dipraglurant was ineffective.
Conclusions
The data demonstrate that transient facial allodynia in rat models of vascular headache and trigeminal sensitization persists for a longer duration in female rats compared to male rats. Clinically effective treatments for headache and migraine, including 5-HT1B/1D receptor agonists and CGRP receptor antagonists, can prevent the development of facial allodynia in preclinical models of headache and trigeminal sensitization in male and female rats. Treatments that are less effective clinically (e.g. NSAIDS) were found to be ineffective in preventing the development of facial allodynia in rat models of headache. Additional studies are currently being performed to further understand the pharmacology associated with these models, and potential future studies will be designed to further characterize behavioral phenotype associated with these models (e.g. photophobia and/or phonophobia).
References
Oshinksy M.L. and Gomonchareonsiri S. (2007) Episodic dural stimulation in awake rats: a model for recurrent headache. Headache 47:1026.
Dallel R., Descheemaeker A. and Luccarini P. (2018) Recurrent administration of the nitric oxide donor, isosorbide dinitrate, induces a persistent cephalic cutaneous hypersensitivity: A model for migraine progression. Cephalalgia. 38:776.
Presenting Author
Mark Urban
Poster Authors
Mark Urban, Ph.D.
PhD
Psychogenics Inc.
Lead Author
Yangmiao Zhang
Ph.D.
PsychoGenics, Inc.
Lead Author
Tolga Berkman
B.S.
PsychoGenics, Inc.
Lead Author
Elizabeth Dugan
Ph.D.
PsychoGenics, Inc.
Lead Author
Katelyn Buban
M.S.
PsychoGenics, Inc.
Lead Author
Jennifer Hagedorn
B.S.
PsychoGenics, Inc.
Lead Author
Anthony Doria
M.S.
PsychoGenics.com
Lead Author
Sarah Woller
Ph.D.
NINDS/NIH
Lead Author
Smriti Iyengar
PhD.
NINDS
Lead Author
Taleen Hanania
Psychogenics Inc.
Lead Author
Topics
- Models: Oral/craniofacial