Psychotomimesis Mediated by [kappa] Opiate Receptors
THE OBSERVATION THAT BENZOMORPHAN [KAPPA] PIOID AGONISTS HAVE ANALGESIC PROPERTIES BUT DO NOT PRODUCE THE DRUG-SEEKING BEHAVIOR OR CARDIOVASCULAR AND RESPIRATORY DEPRESSION SEEN WITH MORPHINE AND OTHER AGONISTS AT [MU] OPIATE RECEPTORS HAS RAISED THE POSSIBILITY THAT SUCH COMPOUNDS COULD BE DEVELOPED FOR USE BY HUMANS (1, 2).
Detailed clinical studies of the actions of [kappa] agonists have been performed with the benzomorphan derivative cyclazocine (3). This opioid, in addition to its [kappa] agonistic activity, has antagonistic properties at [mu] opiate receptors (1-3). Moreover, in humans, cyclazocine and another benzomorphan, N-allyl-normetazocine (Smith Kline & French 10047), elicit psychotomimetic and dysphoric effects similar to those of the dissociative anesthetics phencyclidine (PCP) and ketamine (4). Pharmacological studies suggested that these effects of the [kappa] agonists are mediated by [sigma]-PCP receptors (1, 5, 6). These latter receptors were distinguished from [mu], [delta], and [kappa] opiate receptors by their resistance to the opiate antagonistic naloxone, which classifies them as nonopiate receptors (7). In addition, PCP receptors displayed preference for (+)-isomers, whereas opiate receptors show stereospecificity for (-)-isomers (6, 8). During experiments designed to evaluate endocrine actions (9) of the potent benzomorphan [kappa] agonist MR 2033 (10), which is inactive at [sigma]-PCP receptrs (6), we observed aversive and psychotomimetic effects. Because this observation contradicted the view that [sigma]-PCP receptors mediate psychotomimetic effects of [kappa] agonists, we undertook the present studies to characterize the type of receptor involved. Our results suggest that [kappa] receptors elicit aversive and psychotomimetic actions in humans.
Thirty healthy male volunteers (24 to 62 years old) participated in the experiments. An intravenous cannula was inserted 60 minutes before the drug was administered and the subjects remained in a recumbent position throughout the experiment. Fifteen minutes before intravenous drug injection, the subjects completed five evaluation scales related to mood and physical experiences (11). Observer rating scales were used to assess...
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