Abstract
It is classic reading that the hypothalamus plays a crucial role in the regulation of various physiological homeostatic functions such as autonomic and endocrine control as well as the regulation of sleep and chronicity. In recent years, the characterization of the peptidergic orexinergic system has shed some light on the integrative role of the hypothalamus. The orexins are selectively synthesized in the lateral and posterior hypothalamus and represent a highly specialized neurotransmitter system involved in the hypothalamic regulation of feeding, arousal, wakefulness and the modulation of pain. As the regulation of neuroendocrine functions and nociceptive processing are closely coupled in the hypothalamus, it is not surprising that dysfunction of this regulation is linked to the pathophysiology of a variety of pain disorders, including cluster headache, chronic migraine and medication overuse headache (MOH).
In this issue of Cephalalgia, Sarchielli and colleagues investigate cerebrospinal fluid (CSF) orexin A and corticotrophin-releasing factor (CRF) concentrations in a series of chronic migraine and MOH patients. They report increased levels of CRF and orexin A in chronic migraine and MOH, in keeping with previous findings indicating hypothalamic–pituitary axis alterations (1).
The exact nature of the hypothalamic involvement in primary headache syndromes is not yet clear, and its role in the progression to chronicity is somewhat vague. The hypothalamus is intrinsically linked with a variety of structures involved in pain regulation, including the spinal cord, thalamus, periaqueductal grey and corticolimbic structures involved in the affective and cognitive aspects of pain (2). Similarly, the hypothalamic–pituitary axis plays an important role in the body's response to stress, and specific hypothalamic neuropeptide hormones have been implicated in addiction.
The orexinergic system is emerging as a key component in many hypothalamic functions, including pain, stress and addiction. The findings of increased orexin A in the CSF of chronic migraine and MOH patients is of great interest, as clinical orexinergic data in primary headaches is lacking. A genetic contribution is still not clear, as findings of an orexin receptor polymorphism in cluster headache patients is somewhat controversial (3–5). The findings presented here are probably due to a combination of factors, including an antinociceptive drive, as evidenced by orexin A's ability to inhibit trigeminal nucleus caudalis neuronal responses and neurogenic dural vasodilation in response to dural vasculature stimulation (6–8). The nature of this increased concentration of orexin A remains to be elucidated, as it could possibly result from non-specific rebound hypothalamic activation due to the ascending nociceptive input or a descending modulatory drive.
Corticotrophin-releasing factor CSF levels have been linked to pain levels in fibromyalgia and have been shown to correlate poorly with chronic pain with or without depression (9). The contradiction in results indicates a complex role for CRF in specific pain conditions. It is clear that CRF plays a major role in stress, and it is likely that the stress response to chronic pain in chronic migraine and MOH underlies the observations. Stress activates an opioid-mediated pain modulatory response and chronic stress can lead to central sensitization and hyperalgesia. This sensitization is evidenced with headache patients demonstrating heightened pain elicitation compared with controls in response to stress challenges (10, 11). Further complications arise via the interactions of stress, feeding, sleep and obesity; all risk factors for progression to chronification and systems intrinsically linked to orexinergic function. A further possibility highlighted in the study and overlapping with the former one points to a possible role of drug dependence and motivational state. Hypothalamic–pituitary axis function is altered in persons with dependence on a variety of substances.
Recent research has pointed towards a role for orexin in addictive behaviours. The widespread orexinergic projections include a variety of brain areas implicated in behavioural responses to drugs of abuse (12, 13), and orexin knockout mice demonstrate attenuated morphine dependence and withdrawal (14). The orexinergic–tegmental interaction is considered of great importance in this addictive behavioural response, with orexinergic activation of tegmental dopaminergic neurons likely to result in synaptic plasticity, thus mediating the development, maintenance or re-instatement of addiction.
The association between CRF and orexin and Leeds Dependence Questionnaire scores in MOH patients described here may suggest involvement of these peptides in the motivational state and drug-seeking behaviour in these patients. The orexinergic system may be functionally segregated in components mediating the stress responses, originating in the dorsomedial hypothalamus and in components mediating reward and addiction, originating from the lateral hypothalamus.
It is clear that CRF–orexinergic interaction is complex and is susceptible to a variety of confounding factors including pain, addiction and stress responses. The authors have begun to characterize the involvement of two important hypothalamic peptides in the chronification of migraine and MOH, and further studies are required to investigate the significance and specificity of the findings. Future research looking at the involvement of orexin B may produce interesting results based upon its facilitatory role on trigeminovascular nociceptive transmission in animal studies.