Abstract
Background
Post-traumatic trigeminal neuropathy (PTTN) is a sensory abnormality caused by injury to the trigeminal nerve during dental treatment, for which no effective treatment has been established. However, it is known that abnormal microglial activation in the part of the spinal trigeminal nucleus caudal (Sp5C), where the central trigeminal nerve terminal resides, plays an important role in the pathogenesis of this condition. Cannabinoid CB2 receptor (CB2) is expressed on immune cells including microglia, and its activation has anti-inflammatory effects.
Aims & Objectives
We used a nasal delivery method that allows drugs to be delivered into the brain via the trigeminal nerve. Additionally, we evaluated the effects of CB2 agonists on pain-like behavior and Sp5C microglial changes in a mouse model of PTTN after intranasal administration.
Method
The infraorbital nerve cut (IONC) model was created in 8-week-old male ddY mice by transecting the left suborbital nerve under anesthesia. CB2 agonist HU-308 (30 nmol) and the CB2 inverse agonist SR144528 (100 nmol) were administered via the nasal cavity four times at 8, 10, 12, and 14 days after nerve injury. The response to cold stimuli was assessed by dropping acetone into the cheeks. Morphological changes of microglia in Sp5C were analyzed by immunohistochemical staining.
Results
The current study demonstrated that repeated intranasal administration of HU-308 significantly ameliorates cold hypersensitization and Sp5C microglial activation induced by IONC treatment. Furthermore, pretreatment with the CB2 inverse agonist SR144528 significantly blocked the inhibitory effect of HU-308 on cold hypersensitivity. Additionally, pretreatment with the CB2 inverse agonist, SR 144528, significantly blocked the inhibitory effect of HU-308 on the microglial activation in Sp5C of IONC mice. To evaluate the therapeutic potential of intranasal administration for PTTN, we also investigated an oral administration with an equivalent dose of HU-308, intranasal administration of HU-308 produced a significantly greater effect on cold hypersensitivity compared with oral administration.
Discussion & Conclusions
These data suggest that the intranasal administration of CB2 agonist improved cold hypersensitivity and Sp5C microglial activation following trigeminal nerve injury. Moreover, this study found superior therapeutic effect of the intranasal route. Therefore, treatment of CB2 agonists targeting the trigeminal nerve may be a potential therapeutic candidate for PTTN.