Cerebrospinal fluid levels of orexin-A and corticotropin- releasing factor suggest their involvement in the negative motivational state that driver "drug dependence" in medicational overuse

Background Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), also referred to as orexin-A and -B, are two neuropeptides, which are considered critical components for maintaining and regulating the stability of arousal to mediate the hypothalamic response to stress. Experimental evidence suggests that corticotrophin-releasing factor (CRF) activates the hypocretin system, which relays orexin-A to brainstem nuclei as well as to the extended amygdala, a structure involved in the negative motivational state that drives addiction [1, 2]. No studies have been conducted until now to investigate the role of hypocretins, in particular orexin-A, in medication-overuse headache (MOH). Objective The present study was aimed at investigating the levels of orexin-A and CRF in the cerebrospinal fluid (CSF) of chronic migraine (CM) and probable CM+probable medication-overuse headache (PCM+PMOH) patients. Patients and methods Twenty-five patients affected by CM and 30 patients with a prior history of migraine without aura and diagnosed as having PCM+ PMOH were admitted to the study. Control CSF specimens were obtained from 20 age-matched subjects who underwent lumbar puncture for diagnostic purposes and in all of them CSF and blood tests excluded CNS or systemic diseases. Orexin-A and CRF were determined by radioimmunoassay methods. Clinical variables which were related to CSF levels of orexin-A and CRF were: number of days with headache per month; intensity of headache measured with the visual analogue scale; duration of chronic headache (years); daily drug intake; and Leeds Dependence Questionnaire (LDQ) scores. Results Significantly higher levels of orexin-A and CRF were found in the CSF of PCM+PMOH patients and to a lesser extent in patients with CM compared with control subjects (orexin-A=p<0.001 and p<0.02, =p<0.002 and p<0.0003). A trend toward a significantly positive correlation between CSF levels of orexin-A and CRF emerged in the PCM+PMOH group, but did not reach the level of statistical significance. Asignificantly positive correlation was also found between CSF orexin-A values but not with CRF and daily drug intake and LDQ scores in the latter group (r=0.53, p<0.001 and r=0.48, p<0.002, respectively). In both CM and PCM+PMOH patient groups there was no correlation between number of day with headache per month, intensity of headache and duration of chronic headache. Discussion Results of the present study support the involvement in the orexin-A system mediated by CRF activation, in the negative motivational state that drives drug dependence in MOH. This is supported by the relationship between the number of drugs abused and the scores of a self-completion 10-item instrument (LDQ) to measure dependence upon a variety of substances. These findings suggest a potential role for this hypocretin in driving drug seeking also in MOH through activation of stress pathways in the brain, has been shown in experimental models. References 1. Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–569. Epub 2005 Aug 14 2. Boutrel B, Kenny PJ, Specio SE et al (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102:19168–19173. Epub 2005 Dec 15