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At least 127 records · Page 7Linked to original sources
PubMed1996

Contribution of individual differences to discriminative stimulus, antinociceptive and rate-decreasing effects of opioids: importance of the drug's relative intrinsic efficacy at the mu receptor.

Rats were trained to discriminate 3.0mg/kg morphine from water in a standard two-lever drug discrimination procedure and tested in a hot water tail-withdrawal procedure. When tested with morphine, fentanyl, buprenorphine and butorphanol, individual animals showed a three- to ten-fold difference in the lowest dose that substituted completely for morphine, whereas 30- to 1000-fold differences were obtained with nalbuphine and levallorphan, respectively. Across repeated determinations, the dose-effect curves for morphine and nalbuphine remained relatively stable within an individual, suggesting that the profound individual differences with nalbuphine were not a consequence of variability in the dose-effect curve. In addition, despite the extremely shallow group dose-effect curves obtained with nalbuphine and levallorphan, intermediate levels of drug-appropriate responding were not evidenced in individual animals. In the tail withdrawal procedure, the doses of morphine and fentanyl required to produce the maximal levels of antinociception varied by approximately three-fold across individual rats. With butorphanol and nalbuphine, differences across animals were greater than 30-fold and 300-fold, respectively, whereas with levallorphan, substantial individual differences were observed in the maximal level of antinociception. Further analyses indicated that animals sensitive to the stimulus effects of nalbuphine and levallorphan were also sensitive to the antinociceptive effects of nalbuphine, levallorphan and butorphanol. In contrast to the individual differences obtained with the stimulus and antinociceptive effects of these opioids, the potency of these drugs for decreasing rate of responding was similar across animals. These findings indicate that the relative efficacy of an opioid at the mu receptor is an important determinant of individual differences in responsiveness to its stimulus and antinociceptive effects, but not to its rate-decreasing effects.

Journal Article↗
PubMed1992

Intermediate efficacy mu opioids: examination of their morphine-like stimulus effects and response rate-decreasing effects in morphine-tolerant rats.

The present study examined the effects of morphine, the intermediate efficacy mu opioids (-)-pentazocine, (-)-metazocine, proxorphan, levallorphan, (-)-NANMY (N-allylnormetazocine) and (-)-cyclazocine, and the mu antagonist naloxone 1) in rats responding under a FR (fixed-ratio) 30 schedule before, during and after a chronic morphine regimen, and 2) in rats trained to discriminate 10.0 [10-MS (morphine sulfate)] or 3.0 mg/kg (3-MS) of morphine from saline. Under the FR30 schedule, chronic administration of morphine produced tolerance to morphine's rate-decreasing effects and conferred cross-tolerance to (-)-metazocine, proxorphan and (-)-pentazocine. However, the effects of these intermediate efficacy mu opioids could be differentiated from those of morphine on the basis of their 1) shallow dose-effect curves, and 2) large differences in the degree to which tolerance developed in individual rats. In the drug discrimination procedure, (-)-metazocine, proxorphan and (-)-pentazocine produced high levels of substitution for the 3-MS stimulus and intermediate levels for the 10-MS stimulus. In contrast to the pattern of substitution observed with morphine in the 10-MS group, the effects of these drugs were characterized by 1) shallow dose-effect curves, 2) large individual differences in the lowest dose of each drug that substituted completely for the 10-MS stimulus and 3) the failure to obtain complete substitution for the 10-MS stimulus in all of the rats tested. The behavioral profile obtained with the intermediate efficacy mu opioids (-)-NANM, levallorphan and (-)-cyclazocine was indicative of opioids with intrinsic efficacy lower than that of (-)-pentazocine, (-)-metazocine and proxorphan. Under the FR30 schedule, chronic administration of morphine produced an enhanced sensitivity to the rate-decreasing effects of (-)-NANM and levallorphan but not (-)-cyclazocine. In the drug discrimination procedure, (-)-NANM, levallorphan and (-)-cyclazocine produced high levels of substitution for the 3-MS stimulus and low levels for the 10-MS stimulus. Like naloxone, these drugs produced a dose-related attenuation of the 10-MS stimulus. The results of the present study suggest that the relative order of intrinsic efficacy among the opioids tested is: morphine > (-)-metazocine = (-)-pentazocine = proxorphan > (-)-cyclazocine = levallorphan = (-)-NANM > naloxone.

Animals↗
PubMed1984

Effects of enkephalin and endorphin on the inhibitory junction potentials in the duodenal smooth muscle cells of the guinea-pig.

Inhibitory junction potentials (i.j.p.s) evoked by field stimulation were recorded from the smooth muscle cells of the guinea-pig duodenum intracellularly. The membrane potential was -54.3 mV. The parameters of the i.j.p. were as follows: latency, 71 msec; time to peak, 146 msec; amplitude, 15.5 mV; rate of hyperpolarization, 107 mV/sec; and half decay time of the i.j.p., 193 msec. Met-enkephalin (10(-7)-10(-6) M) had no effect on the membrane potential and the i.j.p. The membrane potential was decreased by beta-endorphin (1.7 X 10(-7)-6.8 X 10(-7) M). Increase in the latency and the time to peak and decrease in the amplitude and the rate of hyperpolarization of the i.j.p. were observed for beta-endorphin. "Spontaneous" excitatory junction potentials (e.j.p.s) were generated by beta-endorphin. Naloxone (3.1 X 10(-6)-3.1 X 10(-4) M) hyperpolarized the membrane of the muscle cells. At high concentrations of naloxone (3.1 X 10(-4) and 3.1 X 10(-3) M), inhibition of the i.j.p. was observed. Levallorphan (2.3 X 10(-4) M) prolonged the latency and the time to peak and reduced the amplitude of the i.j.p. The membrane potential was slightly decreased by levallorphan. "Spontaneous" e.j.p.s were generated by levallorphan in a certain population of the cells. It is concluded that Met-enkephalin does not contribute to the non-adrenergic inhibitory transmission and that beta-endorphin acts as a modulator in the control mechanism of the intestinal motility. The effects of naloxone and levallorphan on the i.j.p. are discussed.

Animals↗