Can chronic pain be suppressed despite purported tolerance to narcotic analgesia?
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Biomedical subjects
Publications and source records attributed to F C Colpaert.
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The ability of cocaine to exert internal stimulus control of behavior was investigated by training rats to discriminate 10 mg/kg cocaine from saline in a discrete-trial, two-lever, food-reward procedure. Acquisition of response control by cocaine (1) succeeded in all animals tested, (2) proceeded rapidly, and (3) was associated with a high Commission Error: Omission Error ratio. These findings support the hypothesis that cocaine, a prototype of drugs inducing a psychotic condition in humans, can act as a powerful internal stimulus in rats. The cocaine cue was also responsive to the action of the dopamine-receptor-blocking agents spiperone (ED50: 0.06 mg/kg), haloperidol (0.24 mg/kg), and pimozide (1.90 mg/kg). d, l-Amphetamine (1.25 mg/kg) induced stimulus generalization with cocaine, and this generalization was blocked by dosages of the same neuroleptics comparable to those of cocaine antagonism. The results are discussed in terms of internal stimulus control of behavior and its relevance to the psychophysiology of schizophrenia.
With a discrete-trial, food-reward, two-lever procedure, rats were trained to discriminate 0.04 mg/kg fentanyl from saline. Individual threshold doses for generalization of fentanyl and for cross-generalization of morphine were determined repeatedly during a 17-week posttraining period. Threshold doses of both drugs almost continuously shifted in both the up- and downward direction. Shifts of fentanyl threshold doses covaried with those of morphine threshold doses. These shifts can best be described by a sustained oscillation, the mean amplitude of which amounts to a factor 3.65 of the dose-range for fentanyl, and to a factor 1.85 for morphine. The upper and lower limits of oscillation were symmetrical with respect to baseline. The oscillation can be described by a function expressing that the more distant a point along the function is from the baseline, the more it is susceptible to (positive/negative) acceleration along the intensity (i.e., dose) axis.
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Rats were trained to discriminate 0.04 mg/kg fentanyl from saline in a 2-lever procedure, and to discriminate 10 mg/kg pentobarbital from saline in a maze procedure. Stimulus generalization experiments in rats trained in this double discrimination indicate that the internal cues produced by these training drugs can be conditioned to the external stimulus conditions associated with the different discrimination procedures.
By using a discrete-trial, two-lever, food-reinforced discrimination learning paradigm, rats were trained to discriminate the narcotic analgesic fentanyl (0.05 mg/kg) from saline. Stimulus generalization experiments with lower fentanyl doses (0.0025 to 0.02 mg/kg) were carried out to generate individual threshold doses. The latter were compared with the sensitivity of the same rats to the analgesic effect of fentanyl, and it was found that there is no correlation between these two sets of data. In a time-effect experiment, the duration of fentanyl's cuing effect was compared with that of its analgesic effect, and it was found that the time-effect characteristics of the narcotic cue are similar to those of analgesia. Again, however, there was no correlation between the duration of both effects within the same group of animals. The results further deliniate the associative and dissociative characteristics of the narcotic cue and narcotic analgesia.
The narcotic cueing activity of sufentanil, fentanyl, morphine and met-enkephalin was studied upon their injection into the lateral brain ventricle of the rat. Comparative studies on the analgesic activity of the three narcotics support a close correlation between the narcotic cueing and the analgesic activity of narcotic drugs.
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Using a discrete-trial, two-lever, food-reward discrimination learning paradigm, we trained rats (n = 6) to discriminate 0.04 mg/kg fentanyl (s.c. t-30') from saline. Stimulus generalization experiments with an adequate dose range (0.01-0.04 mg/kg) of fentanyl revealed that the ED50 value for drug lever selection is 0.02 mg/kg, irrespective of whether the animals were pretreated (s.c., t-60') with either saline or 0.08 mg/kg haloperidol. With increasing doses of the haloperidol-fentanyl combination, the percentage of total responding on the selected lever progressively decreased, and reached the 50% level at the highest drug combination. It is concluded that this percentage is heavily contaminated by factors unrelated to the discrimination condition being studied; these factors seem to invalidate this percentage as a discrimination index under experimental conditions (e.g., behaviorally toxic doses of drugs) where they are likely to operate. The use of response selection as a discrimination index in drug discrimination research is further argued.
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Haloperidol was shown to block the discriminative stimulus properties of electrical stimulation in the lateral hypothalamus, and this effect to be related to train frequency. This finding is relevant to the relation between discriminative and reinforcing properties of stimuli exerting internal stimulus control of behavior.
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