EFFECTS OF LOCAL-ANESTHETICS ON EXPERIENTIAL, PHYSIOLOGICAL AND ENDOCRINE MEASURES IN HEALTHY HUMANS AND ON RAT HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE-RELEASE IN-VITRO - CLINICAL AND PSYCHOBIOLOGIC IMPLICATIONS

Local anesthetics, given i.v. to treat cardiac arrhythmias and for reg ional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals , these drugs activate limbic structures, such as the amygdala, that m ay coordinately regulate sensory processing, mood and pituitary hormon e secretion during stress. Clinically relevant i.v. doses of the short -acting local anesthetic procaine were administered to 17 healthy volu nteers and topographic electroencephalographic (EEG) spectra, stress-r esponsive neuroendocrine and cardiovascular parameters and sensory-cog nitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stre ss and activates limbic structures in experimental animals, the effect s of procaine and lidocaine on immunoreactive CRH release from rat hyp othalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significan t decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, inc luding anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CR H release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of m ood disorders. The electrophysiologic effects of procaine in these vol unteers were analogous to local anesthetic effects in experimental ani mals and consistent with the activation of subcortical structures loca lized within the temporal lobe, such as the amygdala. The effects of p rocaine on stress-responsive neurohormones were similar to those of am ygdala stimulation both in experimental animals and human subjects. Th e in vitro data suggested that procaine-induced pituitary-adrenal acti vation involves stimulation of hypothalamic CRH, although additional ( e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These da ta were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen wi th the systemic use of these agents in clinical practice.