Head pain mechanisms and serotonin in human: A study on m-chlorophenylpiperazine-induced headache and possible no involvement

m-Chlorophenylpiperazine (m-CPP), a 5-HTergic agonist, is a well known migrainous headache provoking agent, probably mediated by NO release. In this study m-CPP was given to 97 subjects, including cluster headache (CH) and migraine patients, to test the hypothesis of an altered 5-HT activity/sensitivity in these pathologies. Sixty-one episodic CH patients, 44 in cluster period and 17 in remission, 10 migraine without aura sufferers, 7 low back pain (LBP) patients and 19 healthy subjects were investigated. A single oral dose of m-CPP, 0.5 mg/Kg, was given. m-CPP plasma levels were not significantly different between the 5 groups. Migrainous headache was reported by 2 healthy subjects (10.5%), 3 cluster period CH patients (6.8%), 2 CH patients in remission (11.7%), 2 migraineurs (20%) and 1 LBP patient (14.2%). Eighteen cluster period CH patients (41%) had a CH attack outside the typical hour of appearance, 2 ±0.2 hours (mean ±sem) after m-CPP administration. This study suggests that 5-HTergic stimulation, in particular of 5-HT2 C/B receptors, play a key role both in migraine and, above all, in cluster headache mechanisms. Nitric oxide release probably is the common factor inducing head pain in both the headache forms.