A major challenge for studying and treating trigeminal pain disorders is the lack of appropriate animal models. While the initial triggering events are different and often cryptic, a common theme for many of the disorders is involvement of the neuropeptide CGRP. In this R21 project, I propose to test the hypothesis that overexpression of CGRP in the mouse trigeminal ganglion will lead to behavioral changes indicative of nociception. The approach will involve delivery of recombinant viruses to the trigeminal ganglion followed by functional assays. We will use intranasal administration to target the trigeminal nerve, which innervates the nasal mucosa. An advantage of this route is that it should deliver virus to the entire trigeminal nerve, including the ophthalmic branch, and connected parts of the CNS while limiting systemic exposure to the viral vector. Combined with the use of a tetracycline regulated promoter system, this approach will allow comparatively localized and acute expression that should minimize compensatory and systemic effects that might occur with a more global transgenic approach. Importantly, the viral approach will also allow us to more readily test different genetic backgrounds, including transgenic mice with additional neuronal CGRP receptor subunits.
Aim 1 will establish and optimize the intranasal viral delivery technique and document the expression of bioactive CGRP.
Aim 2 will involve a thermal sensitivity assay and two aversive behavioral assays as initial tests for whether overexpressed trigeminal CGRP mimics certain trigeminal pain states. A strength of this proposal is its multidisciplinary approach will involve a team of investigators with expertise in CGRP gene expression, intranasal delivery, nociception, and mouse behavior. In the long term, these studies will potentially provide the foundation for mechanism studies and therapeutic strategies for recalcitrant trigeminal-mediated pathologies such as migraine and temporomandibular diseases. The prevalence and severity of trigeminal pain disorders is a significant health issue. Due to the high incidence and generally poor efficacy of current treatments for migraine and all types of trigeminal pain, there is a need for improved therapeutic and preventative measures. Development of a mouse model for trigeminal mediated pain disorders will potentially provide the foundation for testing the efficacy of drugs and therapeutic gene transfer strategies for recalcitrant trigeminal-mediated pathologies such as migraine. ? ? ?
| Zhang, Zhongming; Liu, Xuebo; Morgan, Donald A et al. (2011) Neuronal receptor activity-modifying protein 1 promotes energy expenditure in mice. Diabetes 60:1063-71 |
| Recober, Ana; Kaiser, Eric A; Kuburas, Adisa et al. (2010) Induction of multiple photophobic behaviors in a transgenic mouse sensitized to CGRP. Neuropharmacology 58:156-65 |
| Marquez de Prado, Blanca; Hammond, Donna L; Russo, Andrew F (2009) Genetic enhancement of calcitonin gene-related Peptide-induced central sensitization to mechanical stimuli in mice. J Pain 10:992-1000 |
| Recober, Ana; Kuburas, Adisa; Zhang, Zhongming et al. (2009) Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J Neurosci 29:8798-804 |
| Russo, Andrew F (2007) Ramping it up: RAMP1 and the implications for migraine. Pharmacogenomics 8:687-90 |
