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