Procedures of literature search and study selection

We systematically searched the literature using PubMed and the Scopus Index to explore the hypothalamic contributions to TNP and compare these to migraine and CH. Our search strategy consisted of a computerized review of journal articles without restrictions on publication date, using the keywords “hypothalamus,” “hypothalamic stimulation,” “trigeminal neuropathic pain,” “trigeminal pain,” “orofacial pain,” “migraine,” “cluster headache,” and “pain modulation.”

To provide a thorough analysis, our review included both animal and human studies. Animal studies provided insight into fundamental biological mechanisms and potential experimental treatments, while human studies contributed valuable information on clinical manifestations, imaging results, and therapeutic outcomes. We selected 194 unique entries, applying stringent criteria focused on relevance to our topic and the novelty of findings concerning the hypothalamus’s role in TNP, migraine, and CH (Fig. 1). The first author conducted the screening of papers and identified studies that significantly contributed to our understanding of hypothalamic involvement in these conditions. We selected articles based on discussions of hypothalamic alterations in response to TNP and headache disorders, as well as various neuromodulation techniques targeting the hypothalamus. This review integrates findings on the hypothalamus in TNP, comparing and contrasting its role with that in migraine and CH while ensuring a rigorous selection of relevant literature.

Fig. 1

Flowchart describing the study selection methods. n = number of papers

Structure and connectivity of the hypothalamus

The hypothalamus, located beneath the thalamus as part of the diencephalon, is a highly conserved brain region involved in pain modulation across species, including humans, primates, and rodents [36, 159, 187]. Through complex networks with other brain regions, the hypothalamus plays a crucial role in the central nervous system (CNS) pathways responsible for pain processing. Within the hypothalamus, distinct regions—the anterior hypothalamus (AH), posterior hypothalamus (PH), and lateral hypothalamus (LH)—host specialized nuclei that contribute uniquely to pain processing (Fig. 2). Preclinical and clinical studies have shown that these hypothalamic nuclei project to various cortical and subcortical areas involved in pain modulation, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), periaqueductal gray (PAG), and TNC, with connections mediated by neurotransmitters and neuropeptides like glutamate, GABA, serotonin, histamine, orexin, and endocannabinoids [28, 51, 82, 123, 124, 144, 158, 175].

Fig. 2

Anatomical Location and Connections of Hypothalamus. (A) Location of Hypothalamus (blue area) in the human brain and its subdivisions. (B) Hypothalamic connections with brain regions involved in CNS pain processing pathway and associated neurotransmitters. DH = dorsal hypothalamic area, LH = lateral hypothalamic area, PVN = periventricular nucleus, PH = posterior hypothalamic area, DMN = dorsomedial nucleus, VMN = ventromedial nucleus, AH = anterior hypothalamic area, PN = preoptic nucleus, AN = arcuate nucleus, SN = supraoptic nucleus, SCN = suprachiasmatic nucleus, HPTM = hypothalamus, IC = insular cortex, PFC = prefrontal cortex, MC = motor cortex, SSC = somatosensory cortex, NAc = nucleus accumbens core, TH = thalamus, AMD = amygdala, PAG = periaqueductal gray, PPC = posterior parietal cortex, TNC = trigeminal nucleus caudalis, CBM = cerebellum, ACC = anterior cingulate cortex

In the AH, the paraventricular nucleus (PVN) plays a central role in regulating stress responses and pain through the hypothalamic-pituitary-adrenal (HPA) axis. This interaction influences autonomic responses and cortisol release in the stress animal models, with PVN projections carrying stress-related peptides that facilitate pain-related stress responses [84, 170].

The PH modulates descending pain pathways and maintains essential reciprocal connections with trigeminal pain-processing brain areas. Clinical and preclinical studies indicate that the PH links the hypothalamus to higher-order pain processing and autonomic regulation through serotonin and melanin-concentrating hormone pathways [64, 68, 82, 123, 124, 160].

The LH, meanwhile, contains orexin-producing neurons traditionally associated with energy regulation but also implicated in pain modulation. Chemically-induced rat orofacial pain study has shown that LH’s orexinergic system connects extensively with pain-processing regions, fostering adaptive responses to both internal and external stressors [55, 63].

Differences among TNP, migraine, and CH

TNP is typically caused by direct injury or dysfunction of the trigeminal nerve or its branches and primarily affects one side of the face, often corresponding to the trigeminal nerve distribution. The pain experienced is intensely severe and constant. Nature of pain is often described as burning, throbbing, or aching, often combined with a sensation of numbness or tingling in the affected area. The pain may be triggered by light touch or activities that involve touching or moving the face, such as shaving, eating, or even exposure to air drafts, though it generally lacks systemic symptoms. The sensitization involves activating satellite glial cells and altering sodium and potassium conductance, increasing neuronal excitability. This is accompanied by elevated release of pro-nociceptive neuropeptides like substance P and CGRP, amplifying pain signals relayed to the TNC and ascending through the trigeminothalamic pathway to key brain regions [5, 16, 44]. Standard treatments for TNP include anticonvulsants and nerve blocks, with surgery being an option in more severe cases to alleviate the pain [16, 192].

Migraine is a complex neurological disorder influenced by genetics and environmental factors, with neurovascular disruption, especially in the trigeminovascular system, playing a central role [23]. Migraine pain, typically unilateral and pulsating, may include aura, during which cortical spreading depression (CSD) activates trigeminal fibers and promotes the release of CGRP, substance P, and neurokinin A, causing vasodilation and neurogenic inflammation [32, 37, 157, 169]. Attacks last 4–72 h, often with nausea, vomiting, and sensitivity to light and sound [23, 167]. Sensitization within the TNC may lead to chronic migraine via central sensitization. Triggers include stress, hormonal shifts, diet, sensory stimuli, and environmental changes [145]. Neuroimaging shows altered connectivity between the thalamus, hypothalamus, and prefrontal cortex, indicating maladaptive top-down modulation. Elevated CGRP and TRP channels are key in pain processing and neurovascular responses [43, 59, 89]. Common treatments include triptans and NSAIDs [24, 118].

CH is marked by intense, circadian-patterned pain due to hypothalamic activation, which drives the trigeminal-autonomic reflex [107, 147]. This activation underlies CH’s rhythmic, episodic nature, with attacks often occurring at fixed times. CH is always unilateral, centering around the orbit and temple, with excruciating, piercing, or burning pain lasting 15–180 min, occurring up to eight times daily in bouts lasting weeks or months. Autonomic symptoms—tearing, nasal congestion, and ptosis—are prominent on the affected side [115, 122]. The pathophysiology involves the PH, which triggers parasympathetic outflow via the superior salivatory and trigeminal nuclei [6, 56]. Hypothalamic orexin and hypocretin systems are upregulated, and inflammatory mediators like histamine increase, correlating with CH’s autonomic symptoms. Elevated CGRP and PACAP levels highlight neuropeptide involvement in CH [27, 69, 73]. Imaging reveals altered hypothalamic connectivity with autonomic and pain-processing regions. Triggers include alcohol, strong odors, and histamine release, with attacks often aligning daily during bouts [119]. Treatments include oxygen therapy, triptans, and preventive medications to lessen attack frequency and severity [126, 171].

All three conditions—TNP, migraine, and CH—involve severe, recurrent pain in the head or facial regions. They share common features such as trigeminal system involvement and potential triggers. Despite these similarities, they differ significantly in their pathophysiology, pain characteristics, symptoms, duration, and treatment approaches. TNP typically arises from the peripheral nervous system (PNS), frequently attributed to damage or irritation of the trigeminal nerve. In contrast, some theories suggest that migraine and CHs may primarily involve dysregulations within specific CNS structures; however, this perspective remains under debate, and evidence on the origin of these conditions is not yet conclusive [16, 124, 131]. In cases of TNP, the initial activation occurs at the TNC, followed by subsequent engagement of CNS pathways. Conversely, one prevailing hypothesis suggests that headaches may originate from the activation of nociceptors associated with meningeal blood vessels, which could then trigger the activation of trigeminovascular neurons within the spinal TNC [16, 155].

Pathophysiological differences of hypothalamus in TNP in comparison to migraine and cluster headache

The hypothalamus is integral to the pathophysiology of TNP, migraine, and CH, with distinct activation patterns, neurochemical roles, and neural projections that differentiate its functions across these conditions.

Trigeminal neuropathic pain

In the TNP processing pathway, the hypothalamus is an integral part, with its activation often occurring in relation to or following activation in other pain-processing regions, such as the TNC, thalamus, and primary and secondary somatosensory cortices [38, 61, 190]. However, TNP may not always follow a distinct onset sequence, with pain processing pathways varying based on individual factors and injury characteristics. Chronic constriction injury of the infraorbital nerve (CCI-ION) rat model study has revealed that the hypothalamus could modulate sensory-discriminative and affective-motivational TNP dimensions through neurochemical pathways and its extensive connections with pain-related regions [82]. Central to this process are excitatory glutamatergic mechanisms involving NMDA and AMPA receptors, which contribute to synaptic plasticity and central sensitization, while GABAergic neurons provide inhibitory control over pain thresholds [53, 133]. Additionally, hypothalamic activation influences pain perception via the sympathetic nervous system through vasoconstriction and blood flow adjustment, hormonal modulation through the release of vasopressin, oxytocin, and autonomic as well as endocrine responses; with the HPA axis playing a significant role in regulating pain perception and stress responses in TNP [25, 86, 121, 158, 170].

The PH is central to descending pain modulation in TNP, primarily through GABAergic projections to the ventrolateral periaqueductal gray (vlPAG) and TNC [9, 16, 50, 82]. This modulation involves both pronociceptive and antinociceptive effects mediated by orexin-A and orexin-B peptides, which regulate pain sensitivity within the trigeminal system [71, 74]. Rodent studies have demonstrated that the A11 nucleus, which contains both GABAergic and dopaminergic neurons, exhibits strong bilateral projections to the TNC and becomes activated during facial nociception [1, 2]. In CCI-ION rats, PH activation also shows increased c-Fos, indicating heightened activity during TNP [2, 82, 87].

Chronic Constriction Injury of the Infraorbital Nerve (CCI-ION)

Definition: The CCI-ION model is a well-established preclinical model used to study trigeminal neuropathic pain (TNP). It involves creating a chronic constriction injury in the infraorbital branch of the trigeminal nerve, leading to persistent pain and hypersensitivity.

Procedure: A small skin incision, approximately 7 mm in length, was made along the curve of the frontal bone in an anterior-posterior orientation, positioned 2 mm above the eye of targeted side. The fascia and muscle were carefully separated from the bone using a periosteal elevator while moving laterally. Once the eye was retracted, the infraorbital nerve (ION) became visible on the surface of the maxillary bone. To prepare for ligature placement, about 8 mm of the ION was gently isolated from the surrounding connective tissue. The nerve was then slightly stretched with a blunt needle featuring a curved tip to facilitate ligature placement. Two ligatures were placed 3–4 mm apart, and each was gently tightened until the ION was minimally constricted. The incision was then closed using sutures.

Behavioral Manifestations: Animals exhibit behaviors such as face grooming, avoidance, anxiety and hypersensitivity to mechanical (von Frey test) and thermal stimuli.

Relevance to Humans: The model simulates key features of TNP in humans, including spontaneous pain and allodynia.

Application: CCI-ION model provides insights into TNP mechanisms and the role of specific pathways. CCI-ION model is also used to evaluate potential therapeutic interventions for TNP.

The LH is observed to modulate arousal and pain sensitivity through orexin signalling in clinical studies, with reciprocal projections to the TNC [35, 124]. Dysregulation of orexin and cholinergic signalling in the LH heightened pain sensitivity and altered modulation pathways, exacerbating trigeminal pain disorders in chemical-induced orofacial pain rat model [1, 102, 165, 168].

The PVN enhances stress response via corticotropin-releasing hormone (CRH), influencing the HPA axis. This response intensifies pain chronicity in TNP by releasing stress-induced glucocorticoids, which aggravate pain through neuroinflammatory mechanisms, including microglial activation [17, 28, 33, 179]. Through its ipsilaterally predominant pervicellular and magnocellular neuronal projections to the TNC, the PVN has been observed to impact both ascending and descending pain pathways in clinical and preclinical studies, distinguishing its role from migraine and CH, where it predominantly exacerbates autonomic symptoms [1, 12, 127,128,129, 155].

The SCN regulates circadian rhythms, indirectly modulating pain sensitivity across different times of the day in TNP. Clinical studies indicated that dysregulation in the SCN can lead to variations in pain perception and exacerbation of symptoms, aligning with circadian pain fluctuations often reported in TNP [21, 93, 154].

Dopamine release dysregulation within the ARC influences prolactin secretion and affects emotional responses related to TNP perception in patients with trigeminal neuropathy [5, 104, 120]. Additionally, the periventricular zone, containing opioid and cannabinoid receptors, contributes to endogenous pain control in TNP patient [112]. Alterations in these receptor activities can reduce pain thresholds, affecting endogenous inhibition pathways [66, 120].

These findings collectively highlight the multifaceted role of the hypothalamus in the neural network managing pain, positioning it as a critical target for neuromodulation therapies in seve