Life Sciences, Vol. 33, Sup. I, 1983, pp. 579-581 Pergamon Press Printed in the U.S.A.

A COMPARATIVE STUDY OF THE RESPIRATORY DEPRESSANT AND ANALGESIC EFFECTS OF BRI~TLZOCINE, A K-AGONIST

A. Pazos, C. Tristan and J. Fl6rez

Department of Pharmacology and Therapeutics Faculty of Medicine University of Santander

National Medical Center "M. de Valdecilla", Santander, Spain

(Received in final form June 26, 1983)

Summary

The respiratory depression and analgesia induced by a <-agonist, bremazocine, were studied by the ~Ds0 ratios and the apparent pAz values of the interaction with naloxone. The ratio between the ~Ds0 in respiratory depression and analgesia (i.c.v.) was very high compared to that of other ~- and 6-agonists, indicating its small activity on the respiratory center, pA2 values were 7.33 and 7.20 for analgesia and respiratory depression, respectively, after i.c.v, administration. After s.c. injection, the pA2 value for analgesia was 6.16. The results confirm the involvement of different opiate receptors in the mediation of supraspinal and spinal analgesia. The results suggest that bremazocine may indu- ce analgesia by interacting with different types of receptors located at different levels of the C~S. This property and the low activity on the respiratory center make drugs like bremazoci- ne good candidates in the search for safer opiate analgesics.

Evidence is being accurmalated that the opiate receptors involved in res- piratory depression may be different from those mediating analgesia. Both, ~- and 6-receptors, have been incriminated in the respiratory activity; an in- teraction between the two types of receptors has been also postulated (I ,2). Our previous studies have shown that: I) the ratio between the ~Ds0 of 6-ago- nists required to induce respiratory depression and analgesia is much lower than that of the ~-agonists, and 2) in the case of the 6-agonists, the pAz values for naloxone antagonism against the respiratory depression is higher than that obtained against analgesia, indicating that the population of re- ceptors responsible for the two effects is not hcmogeneous (3,4). Studies of other investigators suggest that the <-receptor does not participate in the respiratory action of opiates, whereas it seems to mediate same types of anal- gesia (5). The <-agonists, therefore, might constitute a safer group of opia- te analgesics. The present study was undertaken to assay the relative effec- tivenes of br~mazocine, a K-agonist (6), in inducing analgesia and respirato- ry depression. Apparent pA2 values were obtained am~, in the analgesic studies, the effects of a central and a systemic route of administration were ccmpared.

~terialsand~thods

Respiration was assessed plethysmographically in lightly anesthetized rats; analgesia was tested by the tail-flick method. The analgesic end point was defined as the latency greater than twice that prior to drug. I.c.v. ad- ministration of br~mazocine (Sandoz) was effected in a volume of 10 ~i. Sys-

0024-3205/83 $3.00 + .00 Copyright (c) 1983 Pergamon Press Ltd.

580 Bremazocine in Analgesia and Respiration Vol. 33, Sup. I, 1983

Table I. Quantitative analysis of naloxone antagonism against bremazocine in respiratory depression and analgesia.

Respiratory Depression

Analgesia (i.c.v.)

Analgesia (s.c.)

Dose of ~Ds0 of agonist Apparent pA2 naloxone (95% confidence limits) values±SiaM (mg/kg) (nmol/animal) (95% conf.

limits)

0.0 1031.0 (606.5-1752.7) 0.01 1434.3 (843.7-2438.3) 7.20±0.05 0.025 2284.4 (1171.5-4454.6) (7.06-7.34)

0.0 10.4 (4.0-27.0) 0.1 76.7 (32.0-184.1) 7.33±0.04 0.3 215.1 (102.4-451.8) (7.21-7.45)

0.0 1.49"(0.55-4.02) 0.1 2.45"(0.91-6.62) 6.16±0.2"* 0.3 2.60*(0.96-7.02) (5.56-6.76)

* in mg/kg. ** significantly different from i.c.v, analgesia (p<.02)

Table II. EDs0 ratios for respiratory depression and analgesia (i.c.v.)

Bremazocine: 99.1

~-agonists Morphine*: 80.5 FK-33824": 11.6

~-agonists D-Ser2-Thr6*: 0.51 DADLE*: 0.07

* Data previously reported

temic administration of drugs was effected s.c. in a dose-volume of I ml/kg. In the antagonism studies with naloxone (pA2 determinations), the time to the peak effect for each dose and effect of bremazocine was considered. ~Ds0 for analgesia and respiratory depression, confidence limits, regression analysis, test for parallelism and validity of the test were estimated by using the pa- rallel line assay of Finney.

Results

Respiratory depression: After i.c.v, administration, bremazocine depres- sed dose-dependently the respiratory frequency; apnea was induced by the highest dose. Tidal volume was not modified. The peak depression was attained very early, at about 3 min. The EDs0 value was 1031.01 nmol/animal (Tabla I).

Analgesic responses: After i.c.v, administration, the peak analgesic effect was obtained dose-dependently in 15-30 rain; the ~D50 value was 10.4 nmol/animal. After s.c. administration, the peak analgesic effect was attai- ned at 30-45 rain; the ~gs0 value was 1.5 mg/kg (Table I).

~Ds 0 ratios: The ratio between the ~3s0 of bremazocine required to de-

Vol. 33, Sup. I, 1983 Bremazocine in Analgesia and Respiration 581

press respiration and to induce analgesia (i.c.v.) was 99.1. For comparative purposes, the ratios obtained with other ~- and 6-agonists, previo~sly repor- ted, are also presented in Table II.

Apparent pA2 values: The apparent pA z values of the interaction of naloxo- ne with bremazocine for analgesia (i.c.v.) and respiratory depression were 7.33±0.04 and 7.20±0.05, respectively (Table I). When bremazocine was adminis- tered s.c., the apparent pA2 value for analgesia was 6.16_+.2, confirming pre- vious results obtained in mice by other investigators (6).

Discussion

The dissociation of the apparent pA2 values, depending on the route of administration, supports earlier contentions that different opiate receptors mediate the spinal and supraspinal analgesia (5). After i.c.v, administration, the pA2 values were similar to those reported for other ~-agonists in both, analgesia and respiratory depression (3). It is possible that, at the supraspi- hal level, bremazocine interacts with ~-receptors preferentially. However, the ~3s0 ratio indicates that bremazocine, even when injected closely to the CNS, has a very modest activity on the respiratory center. Compared to other ~- and 6-agonists, it shows the most favourable ratio in terms of respiratory safety. The low apparent pA2 value obtained after systemic administration indicates that the drug is also interacting with other type of receptors, probably at the spinal level. Low pA2 values have been also reported in the interaction of naloxone with other <-agonists. The selection of drugs with affinities for different receptors involved in analgesia at different levels of the CNS, and with moderate or no activity on receptors related with respiration, must be extremely valuable in the search for safer opiate compounds.

Acknowledgments

Bremazocine was kindly supplied by Dr. R~ner (Sandoz Pharmaceuticals) and naloxone by Endo Laboratories.

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