Reduction of stimulation-produced analgesia by lysergic acid diethylamide, a depressor of serotonergic neural activity

Abstract

MAYER Neurobiology and Anesthesiology Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Md. 20014 and Departments of Physiology and Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Va. 23298 (U.S.A.) (Accepted November 18th, 1976) it is now well known that electrical stimulation of the mesencephalic centrai gray matter in the region of the dorsal raphe nucleus (DRN) produces a profound behavioral analgesia in rat22, 25, cat 26,z8 and monkey 11,a7. In man, stimulation of areas of the periaqueductal gray matter also relieves both chronic clinical and acute experimental pain aS. A number of observations suggest that serotonin participates in the production of this analgesia. Akil and Mayer a have shown that stimulation-produced analgesia (SPA) can be reduced in the rat by p-chlorophenylalanine (p-CPA), a serotonin syn- thesis inhibitor. Reduction in SPA was greater for stimulation sites closer to the DRN, a densely serotonergic neural aggregate 7, thereby further implicating an involvement of this monoamine. Reduction of SPA by p-CPA can also be reversed by the adminis- tration of 5-hydroxytryptophan (5-HTP), the precursor of serotonin 2. Electrical stimulation of the central gray matter has also been shown to have effects at an electrophysiological level. Liebeskind and coworkers ~a,20 have demon- strated in the cat that this stimulation inhibits the responsiveness of dorsal horn lamina V cells to noxious stimuli. They reported that D-lysergic acid diethylamide (LSD) antagonized this inhibition. Although stimulation at many sites within and adjacent to the central gray was effective in inhibiting the responses of lamina V cells to noxious stimuli, LSD greatly reduced the inhibitory effects of only stimulation sites in the immediate vicinity of the serotonergic DRN. Data are also available showing that the closer the electrode is to the DRN of the cat, the greater the magnitude of SPA at a given current intensity a0. These observations, coupled with the demonstration that LSD is a directly acting and potent inhibitor of neural activity of the serotonin-containing neurons of the DRN 14, led us to examine the behavioral effect of LSD on SPA. If LSD were to antagonize SPA it would: (1) provide additional data on the possible role of serotonin systems in this phenomenon and (2) demonstrate that previous electrophysiological observations of the effects of LSD on nociceptive neurons have a behavioral correlate. In these experiments, 90-day-old, male Holtzman rats were implanted with a