SYNOPSISRay and Wolff in a landmark study of human patients under local anesthesia, concluded that the brain was not sensitive to pain; however, at the time of their study, the anatomy and physiology of pain transmission and modulation were largely unknown and their stimulating electrodes were not implanted in the brainstem or thalamic cells or projections now known to be important to pain perception. We now report 15 patients, previously headache-free, who underwent electrode implantation in the periaqueductal gray between 1977 and 1982 who immediately at implantation or in the few days subsequent to implantation reported severe continuous head pain usually with florid "migrainous" feature that persisted for 2 months to 10 years. Ten of these patients were treated with reserpine and all were dramatically responsive to it, but 8 patients rapidly became tolerant. Seven patients who were treated with dihydroergotamine rapidly became headache-free; 2 of the 7 became tolerant quickly. One patient developed the "cough headache" syndrome after implantation, was responsive to indomethacin, the syndrome abating in 6 months. These data suggest that perturbation of brain may generate head pain. (Headache 27:416-420, 1987) Studies performed 45 years ago concluded that the brain is a pain-insensitive structure; 1,2 however, the anatomy and physiology of pain transmission and modulation was not understood at that time, and stimuli were not applied to central nervous system (CNS) sites now known to be important to the perception of pain. Whereas evidence is emerging that migraine and other benign headache disorders are generated by dysfunction of the CNS 3,4 the source(s) of pain has remained unclear. The dogma, based on incomplete data, that the brain is pain-insensitive has stultified hypothesis-testing of CNS mechanisms that might produce head pain.We now report our experience with 15 patients previously headache-free, who underwent electrode implantation in the periaqueductal gray region (PAG) and/or the somatosensory region of the thalamus and immediately or soon thereafter developed headache syndromes that simulated headache disorders that usually arise de novo.

Relief of intractable pain was produced in six human patients by stimulation of electrodes permanently implanted in the periventricular and periaqueductal gray matter. The level of stimulation sufficient to induce pain relief seems not to alter the acute pain threshold. Indiscriminate repetitive stimulation produced tolerance to both stimulation-produced pain relief and the analgesic action of narcotic medication; this process could be reversed by abstinence from stimulation. Stimulation-produced relief of pain was reversed by naloxone in five out of six patients. These results suggest that satisfactory alleviation of persistent pain in humans may be obtained by electronic stimulation.

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✓ The severe spontaneous pain associated with lesions of the central nervous system has been successfully suppressed by electrical stimulation of the posterior limb of the internal capsule. The physiological basis for this result is not understood but the authors's hypothesis is that the pain suppression is due to stimulation of parietal corticofugal inhibitory fibers.

Immunoreactive beta-endorphin was measured in the ventricular fluid of six patients with chronic pain. Stimulation of the periaqueductal gray matter in three patients with pain of peripheral origin resulted in significant increases (50 to 300 percent) in the concentration of ventricular immunoreactive beta-endorphin. In three other patients suffering deafferentation dysesthesia, stimulation of the posterior limb of the internal capsule did not alter the concentration of this peptide. These results provide evidence of the release of human immunoreactive beta-endorphin in vivo and suggest that naloxone-reversible pain relief achieved by stimulation of the periaqueductal gray matter may be in part mediated by the activation of beta-endorphin-rich diencephalic areas.