Mild closed head traumatic brain injury-induced changes in monoamine neurotransmitters in the trigeminal subnuclei of a rat model: mechanisms underlying orofacial allodynias and headache

Abstract

Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.

Keywords: facial and somatic allodynia; headache; migraine; mild to moderate traumatic brain injury; nerve regeneration; neural regeneration; neuromodulators; thermal hyperalgesia; trigeminal sensory system.

Figure 1

Possible neurological sequelae following traumatic brain injury leading to the development of post-traumatic headache. Both trigeminal sensory system and trigeminal vascular system have potential to be affected by the inflammatory molecules and altered expression of excitatory and inhibitory neuromodulators.

Figure 2

Diagram showing the pathways of neuronal connection between various trigeminal subnuclei [spinal trigeminal nucleus oralis (Sp5O), pars interpolaris (Sp5I), pars caudalis (Sp5C) and nucleus tractus solitaries (NTS)], thalamus and sensory cortex. The facial areas with different colors show touch (green), pressure (blue) and temperature (red) related allodynia following traumatic brain injury.

Figure 3

Immunofluorescence staining for 5-HT in the trigeminal subnuclei Sp5O (A), Sp5I (B) and NTS (C). Mild to moderate cTBI altered the expression of 5-HT (red) in Sp5O (–10.84 mm to Bregma), Sp5I (–13.00 mm to Bregma) and NTS (–14.56 mm to Bregma) compared to the corresponding areas of the normal control animals. Scale bar: 50 μm. The position of Bregma was decided according to the rat brain atlas (Paxinos and Watson, 2007). 5-HT: Serotonin; Sp5O: spinal trigeminal nucleus oralis; Sp5I: spinal trigeminal pars interpolaris; NTS: nucleus tractus solitaries; cTBI: closed head traumatic brain injury.

Figure 4

Immunofluorescence labeling of the trigeminal subnuclei Sp5O (A), Sp5I (B) and NTS (C). Mild to moderate cTBI altered the immunoreactivity of DβH (green) and the expression of NK1R (red) in Sp5O (–10.88 mm to Bregma), Sp5I (–13.04 mm to Bregma) and NTS (–14.60 mm to Bregma) compared to the corresponding areas of control animals. Scale bar: 50 μm in all figures. The position of Bregma was decided according to the rat brain atlas (Paxinos and Watson, 2007). cTBI: Closed head traumatic brain injury; DβH: dopamine beta hydroxylase; NK1R: neurokinin 1 receptor; Sp5O: spinal trigeminal nucleus oralis; Sp5I: spinal trigeminal pars interpolaris; NTS: nucleus tractus solitaries.