Direct reticular projections of trigeminal sensory fibers immunoreactive to CGRP: potential monosynaptic somatoautonomic projections

Abstract

Few trigeminal sensory fibers project centrally beyond the trigeminal sensory complex, with only projections of fibers carried in its sensory anterior ethmoidal (AEN) and intraoral nerves described. Fibers of the AEN project into the brainstem reticular formation where immunoreactivity against substance P and CGRP are found. We investigated whether the source of these peptides could be from trigeminal ganglion neurons by performing unilateral rhizotomies of the trigeminal root and looking for absence of label. After an 8–14 days survival, substance P immunoreactivity in the trigeminal sensory complex was diminished, but we could not conclude that the sole source of this peptide in the lateral parabrachial area and lateral reticular formation arises from primary afferent fibers. Immunoreactivity to CGRP after rhizotomy however was greatly diminished in the trigeminal sensory complex, confirming the observations of others. Moreover, CGRP immunoreactivity was nearly eliminated in fibers in the lateral parabrachial area, the caudal ventrolateral medulla, both the peri-ambiguus and ventral parts of the rostral ventrolateral medulla, in the external formation of the nucleus ambiguus, and diminished in the caudal pressor area. The nearly complete elimination of CGRP in the lateral reticular formation after rhizotomy suggests this peptide is carried in primary afferent fibers. Moreover, the arborization of CGRP immunoreactive fibers in these areas mimics that of direct projections from the AEN. Since electrical stimulation of the AEN induces cardiorespiratory adjustments including an apnea, peripheral vasoconstriction, and bradycardia similar to those seen in the mammalian diving response, we suggest these perturbations of autonomic behavior are enhanced by direct somatic primary afferent projections to these reticular neurons. We believe this to be first description of potential direct somatoautonomic projections to brainstem neurons regulating autonomic activity.

A craniofacial-specific monosynaptic circuit enables heightened affective pain

“…Previously Panneton et al injected neural tracer WGA-HRP into the peripheral anterior ethmoidal nerve (AEN), which is originated from TG and innervate the nasal cavity, and observed labeled afferent fibers in regions near PB L 31 . In a follow-up study, the authors showed that trigeminal rhizotomy resulted in loss of CGRP expressing fibers innervating the PB L 30 . These and other studies have implied a possible direct TG→PB L pathway 29 – 32 , but did not provide synaptic or behavior evidence to support this possibility.…”

Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection

“…Several studies suggested a direct connection between the trigeminal ganglion and the parabrachial complex, circumventing the canonical relay site in the spinal trigeminal nucleus ( Panneton et al, 2006 , Cavanaugh, 2011 , Cavanaugh, 2011 , Panneton and Gan, 2014 ). More recently, Rodriguez and colleagues demonstrated a monosynaptic, trigeminal ganglion to PB connection that is implicated in craniofacial pain ( Rodriguez, 2017 ).…”

“…Amplified activity of PB neurons is causally related to chronic pain ( Jergova et al, 2008 , Matsumoto et al, 1996 , Uddin, 2018 , Raver, 2020 ) and changes in PB activity contribute even more heavily in models of craniofacial and orofacial pain ( Rodriguez, 2017 ). Significantly, there exists a direct connection from trigeminal ganglion neurons to PB ( Rodriguez, 2017 , Panneton et al, 2006 , Cavanaugh, 2011 , Cavanaugh, 2011 , Panneton and Gan, 2014 ); bypassing the canonical node in the spinal trigeminal nucleus. Thus, PB is strategically placed to process dura inputs, and to be involved in the pathophysiology of migraine.…”

Repetitive Diving in Trained Rats Still Increases Fos Production in Brainstem Neurons after Bilateral Sectioning of the Anterior Ethmoidal Nerve

“…This rewiring would have to include neuronal plasticity that develops functional connections between non-AEN but nasally-innervating primary afferent fibers and secondary neurons within the MDH. But even if the AEN has a unique afferent input with central projections beyond the trigeminal sensory complex (Panneton and Gan, 2014 ), there must have been a recovery of function in the animals with bilateral sectioned AENs used by Chotiyanonta et al ( 2013 ), since there was a return of the reflex cardiorespiratory responses to nasal stimulation in these anesthetized animals.…”