.vMacmillan Press Ltd, 1992
Br. J. Pharmacol. (1992), 105, 675-678
Inhibitory effect of morphine on yawning induced by cholinoceptor and dopamine D2 receptor activation in rats 1M.R. Zarrindast & A. Jamshidzadeh Department of Pharmacology, Medical Faculty, University of Tehran, Tehran, Iran 1 Bromocriptine (2, 4 and 8mg kg- ',i.p.), physostigmine (0.05, 0.1 and 0.2mg kg- i.p.) and pilocarpine (1, 3 and 5 mg kg- ', i.p.) induced dose-dependent yawning in rats. 2 These responses were reduced in a dose-dependent manner by pretreatment with morphine. 3 The inhibitory effect of morphine was reversed by naloxone. 4 Naloxone alone induced slight but significant yawning. 5 The present results suggest that morphine inhibits yawning in rats at an opiate receptor downstream from the sites at which cholinoceptor and dopamine D2 activation induce yawning. The anatomical location of these sites remains to be established. Keywords: Morphine; pilocarpine; physostigmine; bromocriptine; yawning; dopamine receptors; cholinoceptors
Introduction
Methods
Yawning is a physiological response which is associated with fatigue and recovery from stress (Barbizet, 1958; Stoessl et al., 1987). A number of dopamine agonists including apomorphine and bromocriptine elicited yawning behaviour in rats (Mogilnicka & Klimek, 1977; Baggio & Ferrari, 1983; Zarrindast & Poursoltan, 1989). It has been proposed that this behaviour is mediated via a D2 dopamine autoreceptor (Yamada & Furukawa, 1980; Protais et al., 1983; Baggio & Ferrari, 1983; Zarrindast & Poursoltan, 1989). Central cholinoceptor activation by physostigmine or pilocarpine also induces yawning (Urba-Holmgren et al., 1977; Zarrindast & Poursoltan, 1989). The yawning induced by dopamine agonists and agents acting on cholinoceptors are inhibited by muscarinic antagonists, such as scopolamine and atropine (Mogilnicka et al., 1984; Zarrindast & Poursoltan, 1989). These studies suggest that dopamine receptor agonists induce yawning by activation of the cholinergic system (Carlsson, 1975; Di-Chiara et al., 1976). Links between acetylcholine and dopaminergic neurones have been described in the septor hippocampal system and the striatum (Guyenet et al., 1974; Agid et al., 1975; Storm-Mathisen, 1977) and it has been shown that stimulation and lesion of these structures affect yawning (Jakobartl & Huston, 1977; Dourish & Huston, 1985; Yamada et al., 1986; Stoessl et al., 1987; Laping & Ramirez, 1988). It has also been suggested that dopamine agonists elicit yawning by stimulating dopamine D2 receptors within these structures (Yamada et al., 1986). Opiate interactions with both dopaminergic and cholinergic systems have been demonstrated. There appears to be a close association between opiate receptors and dopaminergic cell bodies and nerve endings in the substantia nigra (LlorensCortes et al., 1979) and striatum (Pollard et al., 1977). Morphine, methadone and other opiates modulate dopaminergic neurotransmission in mesolimbic (Wood, 1983; Iyenger et al., 1987), mesocortical (Kim et al., 1986) and nigrostriatal (Ahtee & Kaariainen, 1973; Gauchy et al., 1973; Costa et al., 1975; Wood et al., 1980) projections. Opiate agonists also inhibit the release of acetylcholine in the central nervous system, an effect which is antagonized by naloxone (Jhamandas et al., 1975). In the present study, we have evaluated the effect of morphine on yawning induced by dopaminergic and cholinergic activation.
Male albino rats weighing 200-250 g, bred in our animal house, were used. The animals were housed in groups of five per cage at a controlled temperature with a 12 h light/dark cycle. Standard laboratory food and tap water were freely available except during the time of the experiments. Prior to the experiments the animals were weighed and placed in individual cages to habituate for at least 30 min.
Author for correspondence.
Statistical analysis Yawning responses were expressed as the mean value. ANOVA followed by Student's t test were used for analysis of the data. Differences between neans were considered statistically significant if P < 0.05.
Drugs The drugs used were bromocriptine mesylate (Sandoz, Switzerland), morphine hydrochloride (MacFarlan, Smith Ltd, England), naloxone hydrochloride (Dupont, Germany), physostigmine salicylate (Sigma, England) and pilocarpine nitrate (Merck, Germany). All drugs were dissolved in water except for bromocriptine which was dissolved in saline with crystalline tartaric acid and a few drops of alcohol. The drugs were prepared immediately before use and were injected in a volume of 1 ml kg
Results The D2 receptor agonist bromocriptine (2, 4 and 8mgkg-1, i.p.) induced yawning in rats (Figure 1). Morphine (1, 2, and 3mgkg-1, s.c., 5min) pretreatment decreased the yawning induced by bromocriptine (8mgkg-1) in a dose-dependent manner (Figure 2). The inhibitory effect of morphine was decreased by naloxone (1.5mg kg-1, s.c., Table 1). Physostigmine (0.05, 0.1 and 0.2mgkg-1, i.p.) induced yawning in rats (Figure 3). Morphine (0.5, 1 and 2mg kg -1, s.c.) administered 5min before physostigmine (0.2mg kg- ', i.p.) dosedependently inhibited physostigmine-induced yawning (Figure 4). The inhibitory effect of morphine on physostigmineinduced yawning was decreased in naloxone (1.5 mgkg- 1) pretreatment (Table 2). Pilocarpine (1, 3 and 5mgkg ', i.p.) also induced yawning behaviour with a maximum response at 3mgkg-1 (Figure 5). Morphine (0.5, 1 and 2mgkg-1, s.c.) dose-dependently decreased the pilocarpine-induced yawning
676
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102 4 8 Bromocriptine (mg kg-') Figure 1 Yawning induced by bromocriptine in the presence or absence of morphine. Rats were injected with bromocriptine (0) and either saline (A, 1 ml kg- , s.c.) or morphine (U, 2 mg kg- 1, s.c.) 5 min before bromocriptine. The number of yawns was recorded for 60min. Each point is the mean for a minimum of eight animals; vertical bars show s.e.mean. Significant differences between the morphine pretreated group and the bromocriptine and bromocriptine plus saline groups are denoted by *P
Br. J. Pharmacol. (1992), 105, 675-678
Inhibitory effect of morphine on yawning induced by cholinoceptor and dopamine D2 receptor activation in rats 1M.R. Zarrindast & A. Jamshidzadeh Department of Pharmacology, Medical Faculty, University of Tehran, Tehran, Iran 1 Bromocriptine (2, 4 and 8mg kg- ',i.p.), physostigmine (0.05, 0.1 and 0.2mg kg- i.p.) and pilocarpine (1, 3 and 5 mg kg- ', i.p.) induced dose-dependent yawning in rats. 2 These responses were reduced in a dose-dependent manner by pretreatment with morphine. 3 The inhibitory effect of morphine was reversed by naloxone. 4 Naloxone alone induced slight but significant yawning. 5 The present results suggest that morphine inhibits yawning in rats at an opiate receptor downstream from the sites at which cholinoceptor and dopamine D2 activation induce yawning. The anatomical location of these sites remains to be established. Keywords: Morphine; pilocarpine; physostigmine; bromocriptine; yawning; dopamine receptors; cholinoceptors
Introduction
Methods
Yawning is a physiological response which is associated with fatigue and recovery from stress (Barbizet, 1958; Stoessl et al., 1987). A number of dopamine agonists including apomorphine and bromocriptine elicited yawning behaviour in rats (Mogilnicka & Klimek, 1977; Baggio & Ferrari, 1983; Zarrindast & Poursoltan, 1989). It has been proposed that this behaviour is mediated via a D2 dopamine autoreceptor (Yamada & Furukawa, 1980; Protais et al., 1983; Baggio & Ferrari, 1983; Zarrindast & Poursoltan, 1989). Central cholinoceptor activation by physostigmine or pilocarpine also induces yawning (Urba-Holmgren et al., 1977; Zarrindast & Poursoltan, 1989). The yawning induced by dopamine agonists and agents acting on cholinoceptors are inhibited by muscarinic antagonists, such as scopolamine and atropine (Mogilnicka et al., 1984; Zarrindast & Poursoltan, 1989). These studies suggest that dopamine receptor agonists induce yawning by activation of the cholinergic system (Carlsson, 1975; Di-Chiara et al., 1976). Links between acetylcholine and dopaminergic neurones have been described in the septor hippocampal system and the striatum (Guyenet et al., 1974; Agid et al., 1975; Storm-Mathisen, 1977) and it has been shown that stimulation and lesion of these structures affect yawning (Jakobartl & Huston, 1977; Dourish & Huston, 1985; Yamada et al., 1986; Stoessl et al., 1987; Laping & Ramirez, 1988). It has also been suggested that dopamine agonists elicit yawning by stimulating dopamine D2 receptors within these structures (Yamada et al., 1986). Opiate interactions with both dopaminergic and cholinergic systems have been demonstrated. There appears to be a close association between opiate receptors and dopaminergic cell bodies and nerve endings in the substantia nigra (LlorensCortes et al., 1979) and striatum (Pollard et al., 1977). Morphine, methadone and other opiates modulate dopaminergic neurotransmission in mesolimbic (Wood, 1983; Iyenger et al., 1987), mesocortical (Kim et al., 1986) and nigrostriatal (Ahtee & Kaariainen, 1973; Gauchy et al., 1973; Costa et al., 1975; Wood et al., 1980) projections. Opiate agonists also inhibit the release of acetylcholine in the central nervous system, an effect which is antagonized by naloxone (Jhamandas et al., 1975). In the present study, we have evaluated the effect of morphine on yawning induced by dopaminergic and cholinergic activation.
Male albino rats weighing 200-250 g, bred in our animal house, were used. The animals were housed in groups of five per cage at a controlled temperature with a 12 h light/dark cycle. Standard laboratory food and tap water were freely available except during the time of the experiments. Prior to the experiments the animals were weighed and placed in individual cages to habituate for at least 30 min.
Author for correspondence.
Statistical analysis Yawning responses were expressed as the mean value. ANOVA followed by Student's t test were used for analysis of the data. Differences between neans were considered statistically significant if P < 0.05.
Drugs The drugs used were bromocriptine mesylate (Sandoz, Switzerland), morphine hydrochloride (MacFarlan, Smith Ltd, England), naloxone hydrochloride (Dupont, Germany), physostigmine salicylate (Sigma, England) and pilocarpine nitrate (Merck, Germany). All drugs were dissolved in water except for bromocriptine which was dissolved in saline with crystalline tartaric acid and a few drops of alcohol. The drugs were prepared immediately before use and were injected in a volume of 1 ml kg
Results The D2 receptor agonist bromocriptine (2, 4 and 8mgkg-1, i.p.) induced yawning in rats (Figure 1). Morphine (1, 2, and 3mgkg-1, s.c., 5min) pretreatment decreased the yawning induced by bromocriptine (8mgkg-1) in a dose-dependent manner (Figure 2). The inhibitory effect of morphine was decreased by naloxone (1.5mg kg-1, s.c., Table 1). Physostigmine (0.05, 0.1 and 0.2mgkg-1, i.p.) induced yawning in rats (Figure 3). Morphine (0.5, 1 and 2mg kg -1, s.c.) administered 5min before physostigmine (0.2mg kg- ', i.p.) dosedependently inhibited physostigmine-induced yawning (Figure 4). The inhibitory effect of morphine on physostigmineinduced yawning was decreased in naloxone (1.5 mgkg- 1) pretreatment (Table 2). Pilocarpine (1, 3 and 5mgkg ', i.p.) also induced yawning behaviour with a maximum response at 3mgkg-1 (Figure 5). Morphine (0.5, 1 and 2mgkg-1, s.c.) dose-dependently decreased the pilocarpine-induced yawning
676
M.R. ZARRINDAST & A. JAMSHIDZADEH
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102 4 8 Bromocriptine (mg kg-') Figure 1 Yawning induced by bromocriptine in the presence or absence of morphine. Rats were injected with bromocriptine (0) and either saline (A, 1 ml kg- , s.c.) or morphine (U, 2 mg kg- 1, s.c.) 5 min before bromocriptine. The number of yawns was recorded for 60min. Each point is the mean for a minimum of eight animals; vertical bars show s.e.mean. Significant differences between the morphine pretreated group and the bromocriptine and bromocriptine plus saline groups are denoted by *P
