Accelerating development of treatments for trigeminal neuralgia using intranasal delivery and a novel behavioral screening device for rats.

Abstract

Orofacial pain disorders are challenging to treat because of poor targeting to the trigeminal, orofacial and brain structures involved. Intranasal administration targets these structures while minimizing systemic exposure and side effects. Lidocaine was intranasally administered to rats, and the trigeminal nerve and trigeminally-innervated structures (teeth, temporomandibular joint (TMJ), and masseter muscle) accumulated up to 20-fold higher tissue concentrations of lidocaine than the brain and blood as measured by ELISA. Intranasally administered infrared dye reached the trigeminal nerve and brain within 10 minutes. Intranasal administration distributed the dye to the trigeminal nerve through three regions with high drug concentrations in the nasal cavity: the middle concha, the maxillary sinus and the choana. These findings indicate that intranasal delivery has the potential to target and treat trigeminal pain disorders with fewer side effects. Such disorders include: tooth pain, TMJ disorder, trigeminal neuralgia, headache, and even certain brain diseases. Although intranasal delivery may aid in targeting approved medications, better novel treatments need to be developed for orofacial pain disorders, specifically trigeminal neuralgia. A new testing device (TrigeminAir) was developed to assist in the screening of trigeminal neuralgia models and treatments. The TrigeminAir device assesses orofacial sensitivity in rats over time by measuring the sip rate of sweetened condensed milk in the presence of a normally non-painful air puff stimulus on the whisker pad. This device detected, 5 to 12 hours after infraorbital nerve injection, that carrageenan (2% or 4%) reduced sip rate by inflaming the whisker pad. During the same time period, intranasal 10% lidocaine (8mg) reversed this reduced sip rate by anesthetizing the inflamed whisker pad. In the first four hours after 4% carrageenan injection, intranasal lidocaine (4% and 10%) decreased neuronal activity in nerves innervating the maxillary teeth, palate, whisker pad and snout. Sensory and motor activity was unaffected after intranasal lidocaine administration, except for anesthesia of the whiskers affecting balance. In conclusion, these results suggest the TrigeminAir device is an efficient and reliable screening method of preclinical models and treatments for orofacial pain and demonstrate that intranasal lidocaine effectively reduces tactile allodynia in rodents. Intranasal delivery and the TrigeminAir device could accelerate the development of new orofacial pain treatments by improving targeting and screening of treatments.