Brain-heart axis in burning mouth syndrome: a neurobiological perspective

TO THE EDITOR

Burning mouth syndrome (BMS) is a chronic intraoral pain condition that is often difficult to diagnose and treat due to its complex and poorly understood pathophysiology [1]. While traditionally considered a localized neuropathic condition, recent evidence suggests it’s a systemic condition driven by central sensitization and autonomic nervous system (ANS) dysfunction [2]. The authors propose that the brain-heart axis, a concept describing the bidirectional communication between the central nervous system (CNS) and the cardiovascular system, provides a critical framework for understanding BMS. Recent research on nociplastic pain offers a valuable framework for understanding BMS [3]. Nociplastic pain arises from altered nociception despite a lack of clear evidence of tissue damage. It involves a mechanism of augmented CNS pain and sensory processing, as well as altered pain modulation. BMS fits this description as it is a chronic regional pain condition whose characteristics align with nociplastic pain criteria [4]. These include the frequent presence of comorbidities such as sleep disturbance, fatigue, anxiety, and depression [5]. These psychiatric comorbidities are not merely consequences of living with chronic pain; emerging evidence suggests they may contribute to the pathophysiology of BMS. The relationship is likely bidirectional: pre-existing psychiatric conditions can lower an individual’s pain threshold, while the chronic pain of BMS can exacerbate symptoms of anxiety and depression, creating a vicious cycle. Like many chronic pain disorders, BMS is characterized by central sensitization, in which increased CNS excitability amplifies pain signals [1–4]. This neuroplasticity, coupled with the frequent co-occurrence of psychiatric comorbidities, suggests a shared neurobiological basis involving the brain’s “pain matrix” and emotional regulation circuits [5]. Chronic pain acts as a stressor that can lead to maladaptive psychological responses. These responses can modulate the ANS, ultimately affecting cardiac function.

The brain and heart are in constant communication via the ANS, which comprises the sympathetic (“fight-or-flight”) and parasympathetic (“rest-and-digest”) branches. In healthy individuals, these branches are balanced, as reflected by high heart rate variability (HRV) [6]. However, in chronic pain states like BMS, this balance is disrupted. Studies have shown that patients with BMS have significantly lower HRV, indicating a state of chronic sympathetic overactivation or parasympathetic withdrawal [7]. This autonomic dysregulation is also a hallmark of other chronic pain conditions, such as fibromyalgia [8] and myofascial pain syndrome [9]. It creates a vicious cycle of pain and physiological instability. Like BMS, these conditions often present with an increased sympathetic response and decreased parasympathetic response, leading to symptoms that resemble those of postural orthostatic tachycardia syndrome (POTS) [10]. The QT interval has attracted attention as an indicator of autonomic dysfunction. In BMS patients, stronger pain catastrophizing is associated with shorter QT intervals [11]. This suggests altered functional connectivity between the ANS and brain networks responsible for processing pain. It also indicates increased tension in the sympathetic nervous system.

While the brain-heart axis provides a valuable general framework, a deeper understanding of BMS requires integrating the unique characteristics of the orofacial/trigeminal system. The trigeminal nerve, which innervates the oral cavity, has distinct features compared to the spinal system. The trigeminal ganglion contains a high density of nociceptive fibers and is directly linked to brainstem nuclei and higher cortical areas [12]. This anatomical and functional specialization means that localized irritation or inflammation in the mouth can rapidly lead to widespread central sensitization and neuroplastic changes, a process known as trigeminal central sensitization [13]. The trigeminal system’s integration with the brain-heart axis is critical. The trigeminal sensory pathways project to various brain regions, including the periaqueductal gray (PAG) and the parabrachial nucleus, which are key components of the descending pain modulatory system and are also involved in autonomic regulation [14]. A hyperactive trigeminal pathway, triggered by central sensitization, can continuously “prime” these regions, leading to persistent sympathetic activation. This sympathetic drive, in turn, can modulate cardiovascular function through the brain-heart axis, as evidenced by the reduced HRV and altered QT intervals seen in BMS patients. The hyperactive sympathetic state then exacerbates the localized burning sensation, creating a feedback loop between the trigeminal pain system and the brain-heart axis. This dysregulation is rooted in large-scale brain networks. In the case of chronic pain, the salience network—which alerts the body to important stimuli—becomes hyperactive. This persistent “threat” signal activates the sympathetic nervous system, putting it in a continuous state of arousal. Concurrently, the default mode network (DMN), which is active during rest and linked to the parasympathetic nervous system, exhibits reduced activity in BMS patients [15]. The result is an imbalance: a hyperactive salience network driving sympathetic arousal coupled with a hypoactive DMN that fails to promote parasympathetic rest.

At the neurochemical level, this network dysfunction is driven by alterations in neurotransmitter systems. Overactivation of N-methyl-D-aspartate (NMDA) receptors contributes to central sensitization and the hyperactive state of the salience network [16]. Furthermore, dysfunction of dopamine D2 receptors is strongly implicated. Similarities observed between BMS and Parkinson’s disease, a condition characterized by dopamine deficiency, suggest that impaired D2 receptor function may disrupt the brain’s natural pain-inhibitory pathways. Medications that reduce basal ganglia dopamine, such as selective serotonin reuptake inhibitors (SSRIs) [17] and angiotensin-converting enzyme inhibitors (ACE-Is) [18], are two major classes of drugs that can induce BMS, supporting this hypothesis. SSRIs and ACE-Is both cross the blood-brain barrier to exert their pharmacological effects on the cortico-basal ganglia loop. As shown in Fig. 1, SSRIs inhibit dopamine release at D2 receptors in the striatum via presynaptic inhibition, thereby blocking the indirect pathway and decreasing dopaminergic output. In contrast, ACE-Is inhibit the enzymatic degradation of substance P, which activates D1 receptors and decreases dopaminergic output via the direct pathway. Thus, both classes of drugs have the potential to decrease dopaminergic output in this critical loop. Studies using positron emission tomography (PET) have shown that patients with BMS have lower levels of D2 receptors and endogenous dopamine in the basal ganglia than healthy controls [19]. The resulting decrease in dopaminergic output leads to functional and structural changes in brain networks. These changes subsequently disrupt the balance of the autonomic nervous system, thereby closing the loop and highlighting the central role of the brain-heart axis in the pathophysiology of BMS.

Fig. 1.

The site of action of drugs that cause Burning Mouth Syndrome on the cortico-basal ganglia loop and the reason for the reduction in dopamine output.

In conclusion, the brain-heart axis is a valuable, objective framework for understanding the systemic nature of BMS. Observed autonomic dysfunction, as measured by heart rate variability, reveals a profound imbalance associated with hyperactivity of the salience network and disrupted connectivity of the default mode network. The neurochemical basis of this dysregulation, particularly the role of dopamine D2 receptors, strengthens this model further. These findings highlight the necessity of shifting our paradigm in understanding and treating BMS. This shift involves moving beyond pharmacological interventions, such as local analgesics and antidepressants, and employing diverse strategies that address underlying neurological and autonomic imbalances. These strategies include receptor-targeted pharmacotherapies combined with cognitive behavioral therapy [20].