Naunyn-Schmiedeberg's Arch Pharmacol (1992) 345:203-208
Naunyn-Schmiedeberg's
Archivesof Pharmacology © Springer-Verlag 1992
Involvement of/ -opioid receptors in the antitussive effects of pentazocine Junzo Kamei, Kiyotaka Katsuma, and Yutaka Kasuya Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hoshi University, 4-4l, Ebara 2-chome, Shinagawa-ku, Tokyo 142, Japan Received August 2, 199l/Accepted November 11,1991
Summary. The effect of pentazocine on the capsaicininduced cough reflex in rats was investigated. Intraperitoneal injection of pentazocine, in doses from 1 to 10 mg/kg, significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of pentazocine (10 mg/kg, i.p.) was significantly reduced by prior injection of naloxone (0.3 mg/kg, i.p.), but it was unaffected by Mr-2266 BS (5 mg/kg, i.p.), an antagonist of •-opioid receptors. The antinociceptive potency of pentazocine (30 mg/kg, i.p.), as determined by the formalin test, was significantly reduced by pretreatment with Mr-2266 BS (5 mg/kg, i.p.), whereas naloxane (0.3 mg/ kg, i.p.) had no significant effect on the antinociceptive effect of pentazocine. The antitussive effects of pentazocine (3 mg/kg) and morphine (0.1 mg/kg) were significantly enhanced in rats treated chronically with naloxone (5 mg/kg/day, 5 days), whereas the antitussive effect of U-50,488 H (1 mg/kg, i.p.), a selective ~c-opioid agonist, was not enhanced in these rats. By contrast, the antinociceptive effect of morphine (0.01 mg/kg, i.p.) was significantly enhanced in rats that had been pretreated chronically with naloxone. However, the antinociceptive effects induced by pentazocine (3 mg/kg, i.p.) and U50,488 H (1 mg/kg, i.p.) were unchanged. These results suggest that pentazocine-induced antitussive effects in rats are mediated via stimulation of #-opioid receptors.
Key words" Pentazocine - Antitussive effect - Cough reflex - Analgesia - Rat
Introduction Pentazocine acts as an opioid agonist-antagonist. Gilbert and Martin (1976) proposed that pentazocine is a competitive antagonist at the #-opioid receptor and an agonist at the ~:-opioid receptor. In general, opioids produce their Send offprint requests to J. Kamei at the above address
effects, such as their analgesic effects, via interactions with three types of receptor (#, 6 and ~c). Previously, we reported that the antitussive effects of opioids are mediated by the #- and ~c-opioid receptors and not by 3opioid receptors (Kamei et al. 1990 a, b). Thus, it appears possible that pentazocine may exert an antitussive effect. The results of studies of the behavioral effects of pentazocine have shown it to have a number of actions in common with morphine (Downs and Woods 1976; McMillan and Morse 1967; White and Holtzman 1982). Such results also suggest that pentazocine has a unique profile of activity among the opioids. Although Levine et al. (1988) recently reported that the analgesic action of pentazocine may be predominantly mediated by ~c-opioid receptors, it is not yet clear which receptors might mediate the antitussive effects of pentazocine. Chronic exposure to opioid antagonists has been demonstrated to increase the number of opioid-binding sites in the brain and to increase the potency of opioid agonists (Bardo et al. 1983a, b, 1984; Lathi and Collins 1978; Tang and Collins 1978; Tempel et al. 1985; Yoburn et al. 1985, 1986). For example, brains of rats exposed chronically to either naloxone or naltrexone exhibit an increase in the number of #-opioid receptors (Bardo et al. 1983a, b, 1984; Lathi and Collins 1978; Tempel et al. 1982, 1984; Yoburn et al. 1985, 1986; Zukin et al. 1982; Zukin and Tempel 1986). Chronic treatment with naloxone or naltrexone also produces an increase in the numbers of 6- or tc-opioid receptors (Millan et al. 1988; Morris et al. 1988). However, naloxone and naltrexone are also known to cause changes in the number of #opioid receptors when administered chronically at doses lower than those needed to produce changes in number of 6- or ~c-opioid receptors (Millan et al. 1988; Morris et al. 1988). If the antitussive and analgesic effects of pentazocine are mediated by a common type of interaction with opioid receptors, it is possible that both the antitussive and analgesic effects of pentazocine in rats, chronically treated with naloxone, might change in the same direction. To test this hypothesis, rats treated chronically with
204 O--
o Respiration
E
Control
50-
Capsaicin
inhalation
o~ 1 0 0
-
I
0
[
15
I
60
I
120min
Respiration Pentazocine 10 m g / k g , i . p . lml
lOs Capsaicin
inhalation
Fig. 1. Typical recording of the effect of pentazocine on the capsaicin-induced cough reflex. Pentazocine (10mg/kg) was administered intraperitoneally (i.p.) 15 min before inhalation of capsaicin (for procedure see Methods). Dots over the recordings of respiration indicate each cough response
Fig. 2. Changes with time in the effect of pentazocine, at doses of 3 mg/kg (O) and 10 mg/kg (O), on the number of coughs. Each point represents the mean with SE (n = 5) of the percent reduction of the number of coughs. Significant differences from saline (D) value of each test time are indicated as *P < 0.05
Table 1. Influence of naloxone and Mr-2266 BS on the effects of pentazocine on the number of coughs, 15 rain after i.p. administration of pentazocine. The data represent the means _4-SE (n) of the percent reduction in the number of coughs. Naloxone or Mr-2266 BS was injected i.p. 5 min before administration ofpentazocine. For absolute values see text
n a l o x o n e w e r e s u b s e q u e n t l y t e s t e d f o r t h e i r r e s p o n s e to the a n t i t u s s i v e a n d a n a l g e s i c effects o f p e n t a z o c i n e .
Dose % Inhibition of the number of coughs (mg/kg) ControI Naloxone Mr-2266 BS (0.3 mg/kg) (5 mg/kg)
Methods
Animals. Male Sprague-Dawley rats obtained from Tokyo Animal Laboratory Inc., Tokyo, Japan, weighing about 250 g (8 weeks old) at the beginning of experiments were used. Animals were housed in groups of seven in cages in which food and water were continuously available, in a temperature-controlled (22 _+ 1° C) animal room, for at least 4 days before experiments. Each animal was used only once. Antitussive assay. The cough reflex was induced by the method described previously (Kamei et al. 1989). In brief, animals were exposed to a nebulized solution of capsaicin (30 pmol/1, under identical conditions, using a body plethysmograph. The aerosols were produced with an ultrasonic nebulizer, and inhaled using a artificial ventilator at a constant volume (20 ml) and a frequency of 30 times/ rain. About 0.6 ml of solution was nebulized per min. The number of coughs produced per 5-min period of exposure to capsaicin was counted. The rats were exposed to capsaicin 30 rain before injection of drugs to determine the frequency of control coughs, then they were exposed to capsaicin ] 5 min after i.p. injection of either a drug or vehicle. The number of coughs produced 15 min after the injection of a drug was compared with the number produced by vehicie-injected control rats. The antitussive effect was expressed in terms of the percentage reduction in number of coughs relative to the number of control coughs. Antinociceptive assay. The formalin test was used to measure the nociceptive threshold. In the formalin test, 0.02 ml of a 1% solution of formalin was injected s.c. into the dorsal surface of the rat's right hindpaw, 15 min after administration of vehicle or each test drug. The rat was then placed in a Plexiglas observation box (25 by 25 by 35 cm3), and its nociceptive responses were recorded. The time of injection was taken as zero time, and observations of behavior started immediately after the injection of formalin. The total amount of time (in seconds) spent in licking and biting the injected paw during the course of 2 min was taken as an indicator of nociception. Chronic treatment with naloxone or morphine. Naloxone, at a dose of 5 mg/kg, s.c., was injected once a day (at 15:00) for 5 days.
Saline Pentazocine 1 3 10
4.3 _-4-1.9(5) 21.9-+ 3.2(5) ~ 45.4 -+ 6.6(5)" 75.7 -+ 8.8(5)" 40.1 _+4.9(5) b 75.7_+4.9(5)
a Significantly different (P < 0.05) from the saline value b Significantly different (P < 0.05) from the control value
Morphine, at a dose of I mg/kg, was injected i.p. twice a day (10 : 00 and 16:00) for 4 days. Control animals were similarly treated, but received physiological saline instead of naloxone or morphine. On day five (for morphine-treated rats) or day six (for naloxone-treated rats), antitussive and antinociceptive assays were performed. Drugs. The drugs used were pentazocine hydrochloride (Yamanouchi Pharmaceutical Co., Tokyo, Japan), morphine hydrochloride (Sankyo Co., Tokyo, Japan), U-50,488H {trans(_+)-3,4-dichloroN - methyl - N - [2 - (1 - pyrrolidinyl)cyclohexyl] - benzeneacetamide} (Upjohn Company, Kalamazoo, Mich., USA), naloxone hydrochloride (Sigma Chemical Co., St. Louis, Mo., USA) and Mr-2266 BS [(-)-2-(3-furylmethyl)-noretazocine] (Boehringer Ingelheim KG, Ingelheim, FRG). All doses refer to the salt forms of the drugs. Mr-2266 BS was dissolved in 0.01 N HC1 and the pH was adjusted to between 4 and 5 with an appropriate amount of a solution of NaOH. All other drugs were dissolved in 0.9% saline. Statistical analysis. Data are expressed as the mean _+ SE. Statistical analyses were performed by analysis of variance with Student's ttest or Dunnett's test. Results
A n t i t u s s i v e effects F i g u r e 1 s h o w s t y p i c a l r e c o r d i n g s o f t h e effects o f p e n t a z o c i n e (10 m g / k g , i.p.) o n t h e c o u g h reflex. I n Fig. 2,
205 Table 2. Influence of naloxone and Mr-2266 BS on the analgesic effects of pentazocine in the formalin test, 15 min after i.p. administration of pentazocine. The data represent the means + SE (n) of the duration (s) of the pain response over the course of 2 rain. Naloxone or Mr2266 BS was injected i.p. 5 min before administration of pentazocine Dose (mg/kg)
Duration of pain response/2 min (s) Control
Saline Pentazocine
3 10 30
67.9 +_2.1 (5) 56.7 ± 7.2(5) 27.0 ± 5.4(5)a 8.8 +_5.1 (5)"
Naloxone (0.3 mg/kg)
Mr-2266 BS (3 mg/kg)
Mr-2266 BS (5 mg/kg)
4.8 _+4.1 (5)
29.0 -t- 3.2(5)b
35.1 ± 3.4(5)b
a Significantly different (P < 0.05) from the saline value b Significantly different (P < 0.05) from the control value
the time course of the effects of i.p. administration of pentazocine on the number of coughs shows that the cough depressant effect reached its peak 15 min after the administration of pentazocine, at a dose of 3 mg/kg, and a return to control values was achieved within 120 min. With a dose of 10 mg/kg, the maximum decrease in the number of coughs was also apparent 15 min after i.p. administration of pentazocine. After 120 min, the number of coughs remained significantly lower in rats treated with pentazocine (10 mg/kg) than in control rats that received saline. Thus, a time interval of 15 min after the injection o f pentazocine was chosen for experiments designed to quantitate the effects of pentazocine on the cough reflex. As shown in Table 1, pentazocine, at doses from 1 mg/kg to 10 mg/kg, significantly decreased the number of coughs. The absolute numbers (coughs/5 min; each n = 5) were: before saline injection, 27.4 ± 3.2; after saline injection, 2 5 . 4 ± 1.8; before i mg/kg of pentazocine, 22.8 ± 5.0; after 1 mg/kg of pentazocine, 18.0_+4.3; before 3 mg/kg of pentazocine, 2 7 . 2 ± 6 . 9 ; after 3 mg/kg ofpentazocine, 14.4 ± 3.5; before 10 mg/kg ofpentazocine, 26.0 ± 1.1 ; after 10 mg/kg ofpentazocine, 6.7 ± 2.5. This shows a highly significant correlation (r = 0.972; P < 0,01) between the percentage reduction in the number of coughs and the dose of pentazocine. The cough-depressant effect of pentazocine (10 mg/kg) was significantly reduced by pretreatment with naloxone (0.3 mg/kg, i.p.), whereas pretreatment with Mr-2266 BS (5 mg/kg, i.p.) had no significant effect on the coughdepressant effects of pentazocine.
Antinociceptive effects In saline-treated rats the mean duration of nociceptive responses (paw licking or biting) over the 2 rain that followed injection of formalin was 67.9 + 2.1 s (n = 5). Pentazocine ( 3 - 3 0 mg/kg) injected i.p. caused a doserelated (r = 0.918, P < 0.01) reduction in the nociceptive response time (Table 2). This effect of pentazocine (30 mg/kg) was significantly reduced by pretreatment of rats with Mr-2266 BS, in a dose-dependent manner (Table 2). In contrast, the antinociceptive effect of pentazocine (30 mg/kg) was not influenced by pretreatment of rats with naloxone (0.3 mg/kg, i.p., Table 2).
100-
o u o E == 50==
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Pentazocine 3 mg/kg
Morphine 0.1mg/kg
U - 5 0 488H I mg/kg
Fig. 3. Effects of chronic treatment with naloxone (5 mg/kg/day, i.p., for 5 days; N) on the antitussive effects of pentazocine, morphine and U-50,488H. Each column represents the mean with SE (n = 5) of the percent reduction in the number of coughs, 15 min after administration of each drug. Significant differences from the saline-treated ([]) group are indicated as *P < 0.05. For absolute values see text
Effects of chronic treatment with naloxone or morphine on the antitussive and antinociceptive effects of pentazocine As shown in Fig. 3, the antitussive effect of pentazocine (3 mg/kg) was markedly enhanced in rats chronically treated with naloxone (5 mg/kg/day, 4 days) (chronic saline, 16.3 __ 1.8 coughs/5 min vs. 10.3 ± 2.4 coughs/ 5 min, n = 5; chronic naloxone, 23.5 ± 3.5 coughs/5 min vs. 2.2 ± 0.7 coughs/5 rain, n = 5). The antitussive effect of morphine, at a dose of 0.1 mg/kg, was also significantly enhanced in these naloxone-treated rats (chronic saline, 16.4 ± 3.0 coughs/5 min vs. 11.2 ± 2.7 coughs/5 min, n = 5; chronic naloxone, 22.5_+5.5 coughs/5min vs. 3.8 ± 1.1 coughs/5 rain, n = 5) (Fig. 3). However, chronic treatment with naloxone did not significantly influence the cough-depressant effect of U-50,488H (1 mg/kg), a specific agonist of ~c-opioid receptors (chronic saline, 16.4 ± 4.5 coughs/5 rain vs. 8.8 ± 1.0 coughs/5 rain, n = 5; chronic naloxone, 23.2_+5.9 coughs/5min vs. 8.4 _+ 2.1 coughs/5 min, n = 5) (Fig. 3). By contrast, the antitussive effects of pentazocine (10 mg/kg) (chronic saline, 20.8 _ 1.3 coughs/5 rain vs. 5.4 ± 1.0 coughs/
206 100--
100 --
1 ~
!
50--
!
~"
oPentazocine 10 mg/kg
Morphine 0.3 mg/kg
U-50,488H lOmg/kg
Fig. 4. Effects of chronic treatment with morphine (1 mg/kg, twice a day i.p., for 4 days; gg) on the antitussive effects of pentazocine, morphine and U-50,488H. Each column represents the mean with SE (n = 5) of the percent reduction in the number of coughs, 15 min after administration of each drug. Significant differences from the saline-treated (~) group are indicated as *P < 0.05. For absolute values see text
100
-
®
o@ Pentazocine lOmglkg
Morphine O.03mg/kg
U-50,488H 3 mg/kg
Fig. 6. Effects of chronic treatment with morphine (1 mg/kg, twice a day i.p., for 4 days; []) on the antinociceptive effects ofpentazocine, morphine and U-50,488H. Each column represents the mean with SE (n -- 5) of the duration (s) of the pain response over the course of 2 min, 15 rain after administration of each drug. Significant differences from the saline-treated group ([]) are indicated as * P < 0.05
sponse times in formalin-treated rats were not significantly affected by chronic pretreatment with naloxone (Fig. 5). By contrast, the analgesic effect of morphine (0.1 mg/kg), but not those ofpentazocine and U-50,488H were significantly reduced in rats chronically treated with morphine (1 mg/kg, i.p., twice a day for 4 days; Fig. 6).
-
w .E E
.=_
50-
50-
Discussion
Pentazocine 3 n~jlkg
Morphine O.01mglkg
U-50,488H I mglkg
Fig. 5. Effects of chronic treatment with naloxone (5 mg/kg/day, i.p., for 5 days; []) on the antinociceptive effects of pentazocine, morphine and U-50,488H. Each column represents the mean with SE (n = 5) of the duration (s) of the pain response over the course of 2 min, 15 rain after administration of each drug. Significant differences from the saline-treated group (S) are indicated as *P < 0.05 5 rain, n = 5; chronic morphine 29.8 + 4.2 coughs/5 min vs. 1 3 . 6 _ 2.5 coughs/5 rain, n = 5) and of morphine (0.3 mg/kg) (chronic saline, 20.6 ± 2.7 coughs/5 rain vs. 6.3 ± 1.2 coughs/5 rain, n = 5; chronic morphine, 21.0 ± 1.8 coughs/5 min vs. 13.9 ± 0.9 coughs/5 rain, n = 5), but not those of U-50,488H (10 mg/kg) (chronic saline, 21.4 _+ 2.4 coughs/5 rain vs. 6.7 _+ 1.1 coughs/ 5 min, n = 5; chronic morphine, 24.2 + 1.9 coughs/5 min vs. 5.9 + 1.4 coughs/5 min, n = 5), were significantly reduced in rats chronically treated with morphine (1 rag/ kg, i.p., twice a day for 4 days; Fig. 4). The antinociceptive potency of pentazocine was also examined in rats chronically treated with naloxone (Fig. 5). Chronic treatment with naloxone significantly enhanced the antinociceptive effect of morphine, at a dose of 0.01 mg/kg. However, the effects of pentazocine (3 mg/kg) and U-50,488H (1 mg/kg) on nociceptive re-
The results of the present study indicate that pentazocine produces a potent and dose-related antitussive effect in rats. Pentazocine has been classified as an antagonist at #-opioid receptors and an agonist at ~c-opioid receptors (Gilbert and Martin 1976; Martin 1983). Previously, we reported that the antitussive effects of opioids are mediated by the #- and ~-opioid receptors, and not by 6opioid receptors (Kamei et al. 1990a, b). Thus, it was reasonable to speculate that pentazocine exerts its antitussive effect via stimulation of tc-opioid receptors. In the present study, however, the pentazocine-induced antitussive effect was reversed by a low dose of naloxone (0.3 mg/kg), but it was unaffected by Mr-2266 BS (5 mg/ kg), which has been reported to be a relatively selective antagonist of tc-opioid receptors with little #-opioid receptor antagonistic effect (Jackisch et al. 1986; Kosterliti et al. 1981). Moreover, the antitussive action of pentazocine was markedly reduced by naloxone (0.3 mg/ kg), whereas the antinociceptive action of pentazocine was not influenced by naloxone at the same dose. Naloxone acts as an antagonists at #-, 6- and ~c-opioid receptors, but a higher dose of naloxone is required to antagonize the effects of 6- and ~c-opioid receptor agonists than those of #-opioid receptor agonists (Gilbert and Martin 1976; Kosterlitz et al. 1981). Thus, it appears possible that the antitussive action of pentazocine is mediated mainly via stimulation of #-opioid receptors. This hypothesis is strongly supported by the observation that the pentazocine-induced antitussive effect was markedly
207 enhanced in rats that had been chronically treated with naloxone. Morris et al. (1988) reported that chronic treatment with naloxone induced the upregulation of #-, 6and ~:-opioid receptors. It was also reported that chronic treatment with naloxone produced a supersensitivity to morphine analgesia and that this supersensitivity was related to upregulation of #- and 6-opioid receptors (Bardo et al. 1984; Yoburn et al. 1986, 1988). In the present study too, the antitussive action of morphine, but not the action of U-50,488H, a selective agonist of ~copioid receptor, was significantly enhanced by chronic treatment with naloxone. Furthermore, we reported previously that 6-opioid receptors are not involved in the antitussive effects of opioids (Kamei et al. 1990b), and that tolerance to the antitussive effect of morphine developed in rats that had been chronically treated with morphine (1 mg/kg, twice a day for 4 days; Kamei et al. 1991). However, in rats made tolerant to morphine, there was no cross-tolerance to U-50,488H (Kamei et al. 1991). In the present study, we also found that tolerance to the pentazocine-induced antitussive effect developed in rats made tolerant to morphine. It is, therefore, suggested from our results that the enhancement of the pentazocineinduced antitussive effect in rats chronically treated with naloxone is attributable to the upregulation of #-opioid receptors. The antinociceptive action of pentazocine was significantly reduced by Mr-2266 BS, in a dose-related manner, but not by naloxone. Furthermore, the analgesic effect of pentazocine was not influenced by chronic treatment with naloxone, whereas the morphine-induced analgesic effect was markedly enhanced. In chronically naloxonetreated animals, the analgesic effect induced by U50,488H was also unchanged. In the present study, furthermore, we found that tolerance to the morphine-induced analgesia, but not pentazocine- and U-50,488Hinduced analgesia, developed in rats made tolerant to morphine. These findings support the suggestion that pentazocine-induced analgesic activity is mediated mainly via interaction with the receptors with which U50,488H also interacts, namely, ~c-opioid receptors. The results of the present study lead us to the hypothesis that morphine and pentazocine act on the same receptors to produce depression of the cough reflex, while pentazocine produces analgesia via interaction with different receptors. In other words, the antitussive effect of pentazocine is mediated by #-opioid receptors, while pentazocine-induced analgesia is mediated mainly by interactions with ~c-opioid receptors. In this regard, McGilliard and Takemori (1978) have suggested, on the basis of apparent pA2 values, that morphine and pentazocine act via interactions with separate receptors to produce their analgesic effects, while they may act similarly on specific receptors to produce their respiratory effects. This suggestion strongly supports our hypothesis. However, the reason for the differences in the specific receptors or in the receptor interactions between those that mediate the pentazocine-induced antitussive effect and those that mediated the analgesic effect is not clear. Pentazocine has affinity for #-, 6- and tc-opioid receptors. The rank order of its affinity for the various receptors is
# (D-Ala 2, MePhe 4, Gly-olZ-enkephalin) > ~c (ethylketocyclazocin) > 6 (D-Ala 2, D-LeuS-enkephalin) sites (Magnan et al. 1982). Pasternak and Wood (1986) proposed that #l-opioid receptors mediate analgesia supraspinally, while #z-opioid receptors are involved in respiratory depression. If # 1-opioid receptors are not able to recognize pentazocine, the drug may stimulate the ~c-opioid receptor systems in analgesia. It seems likely, therefore, that pentazocine acts mainly as an agonist at the g/-opioid receptors, which are involved in the central integrating neuronal mechanisms of the cough reflex, whereas pentazocine produces analgesia mainly via ~copioid receptors. This possibility appears to provide a very plausible explanation for the observation that pentazocine has antitussive and analgesic effects that are mediated by different receptors or receptor interactions. In the present study, furthermore, we observed that the dose of pentazocine for analgesia is relatively higher than that for the antitussive action (Table 1 and Table 2). This finding also supports our hypothesis.
Acknowledgements. We are grateful to Upjohn Company for the gift of U-50,488H, and to Boehringer Ingelheim for the gift of Mr-2266 BS. References
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