Locus coeruleus-noradrenergic modulation of trigeminal pain: Implications for trigeminal neuralgia and psychiatric comorbidities

Abstract

Trigeminal neuralgia is the most common neuropathic pain involving the craniofacial region. Due to the complex pathophysiology, it is therapeutically difficult to manage. Noradrenaline plays an essential role in the modulation of arousal, attention, cognitive function, stress, and pain. The locus coeruleus, the largest source of noradrenaline in the brain, is involved in the sensory and emotional processing of pain. This review summarizes the knowledge about the involvement of noradrenaline in acute and chronic trigeminal pain conditions and how the activity of the locus coeruleus noradrenergic neurons changes in response to acute and chronic pain conditions and how these changes might be involved in pain-related comorbidities including anxiety, depression, and sleep disturbance.

Keywords: Locus coeruleus; Neuropathic pain; Noradrenaline; Trigeminal neuralgia.

Fig. 1

Simplified schematic representation of noxious transmission from face and head to upper brain regions involved in pain modulation. (1) Ophthalmic, maxillary, and mandibular branches of the trigeminal nerve carry noxious sensations from the head and face to the trigeminal ganglion (TG). (2) TG neurons constitute the first-order neurons and nociceptive unmyelinated C and lightly myelinated A-delta fibers coming from the TG are distributed to (3) the trigeminal sensory nuclear complex (TSNC). The TSNC comprises the spinal nucleus and main sensory nucleus. The spinal nucleus consists of three subnuclei: subnucleus oralis, interpolaris, and caudalis. In the TSNC, orofacial nociceptive afferents synapse on second-order neurons, and (4) these neurons then form the ventral trigeminothalamic tract and synapse with third-order neurons in the ventral posteromedial nucleus (VPM) of the thalamus. (5) From the thalamus, nociceptive information is conveyed to the primary and secondary somatosensory cortices. The periaqueductal gray (PAG) and the rostral ventrolateral medulla (RVM) are the two key brain regions that mediate descending pain modulation. The locus coeruleus (LC) receives inputs from the PAG and the RVM and sends inhibitory projections to the TSNC. Adapted from “Discriminative Pain Pathways”, byBioRender.com(2023). Retrieved fromhttps://app.biorender.com/biorender-templates.

Fig. 2

Locus coeruleus-noradrenaline mediated actions in trigeminal ganglia (TG) and subnucleus caudalis. Adapted from “Distribution of Norepinephrine Neurotransmitters in the Human Brain”, byBioRender.com(2023). Retrieved fromhttps://app.biorender.com/biorender-templates.