Different responses of nitric oxide synthase inhibition on morphine-induced antinociception in male and female rats

Pathophysiology 18 (2011) 143–149

Different responses of nitric oxide synthase inhibition on morphine-induced antinociception in male and female rats Mahmoud Hosseini a,∗ , Zahra Taiarani b , Mosa Al-Reza Hadjzadeh a , Soodabeh Salehabadi b , Maryam Tehranipour b , Hojjat Allah Alaei c a

Department of Physiology and Pharmacological Research Center of Medicinal Plants, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran b Department of Biology, Faculty of Science, Islamic Azad University, Mashhad Branch, Mashhad, Iran c Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Received 28 June 2009; received in revised form 16 November 2009; accepted 18 May 2010

Abstract The roles of gonadal hormones and nitric oxide on pain perception and their interaction have been widely investigated. In the present study the chronic effect of l-NAME (NOS inhibitor) on morphine-induced antinociception in male and female rats was investigated. Forty rats were divided into four groups: (1) female (2) female-LN (3) male (4) and male-LN. The animals of groups 2 and 4 received daily injection of l-NAME (10 mg/kg) during 3 weeks. The animals of control groups 1 and 3 received 2 ml/kg saline instead of l-NAME. Finally, all animals were tested on the hot plate test (52 ± 0.2 ◦ C; Cut-off 80 s) to evaluate the antinociceptive effects of morphine. The hot plate test was performed for base record 15 min before the injection of morphine (10 mg/kg; s.c.) and consequently it was repeated every 15 min after the injection. There were no significant differences in baseline latencies among all groups. Reaction times after injection of morphine in female-LN were higher than in the female control group (p < 0.01). There was, however, no significant difference between male control and male-LN groups. Reaction times in the female-LN group were significantly higher than in the male-LN group. Reaction times after injection of morphine in the male group was longer than in the female group (p < 0.01). It is concluded that sex hormones such as testosterone and estrogen have a role in pain perception and analgesia. NO has a modulatory effects on functions of sex hormones in pain perception and analgesic effects of opioids. © 2010 Elsevier Ireland Ltd. All rights reserved. Keywords: l-NAME; Sex; Morphine; Pain; Rats

1. Introduction Pain is an unpleasant sensation which is elicited by exposure of skin and other organs to damaging or potentially damaging, noxious stimuli [1]. Several factors such as sociocultural, psychological and biological conditions affect pain perception [2]. There is now strong evidence for sex differences in pain and analgesia [3–7]. Migraine, fibromyalgia and temporomandibular joint disorder which are accompanied with chronic pain, have a higher prevalence in females in comparison with males [8,9]. These differences have been attributed to modulatory effects of gonadal hormones such as estradiol and testosterone on pain or analgesia [3,10–13]. The ∗

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0928-4680/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pathophys.2010.05.004

presence of estrogen receptors in areas of the brain that are related to pain, imply that sex hormones have a role in pain perception or analgesia [14]. High localization of estrogen receptors in periaqueductal gray (PAG) confirms that estrogens influence the function of descending analgesia pathways [15,16]. Progestrone receptors are also present in the ventrolateral medulla, the reticular formation and the nucleus of the solitary tract and thus, progestrone probably has a role in pain processing [17]. The interaction of estrogen with neurotransmitters such as gamma amino butyric acid (GABA), serotonin and calicitonin gene-related peptide (CGRP) may also contribute to the sex differences in pain modulation [18–20]. Reduction in pain sensitivity after injection of testosterone in animal models has also been reported [21]. Therefore, the role of androgens in sex-dependent difference of pain should not be ignored.

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Sex differences in opioid antinociception have also been widely reported [22–24]. Animal studies suggest greater opioid analgesia for males [7] while some of human studies indicate that opioids may exhibit more analgesia in females [25]. Nitric oxide (NO), as a major neurotransmitter, is involved in nociceptive processing [26]. It has been reported that NO donor enhances the release of the neuropeptides such as substance P and CGRP which have a role in pain transmission [27]. It has been also found that NO synthase inhibitor reduces the c-fos expression induced by noxious mechanical stimuli [28]. In contrast, some studies have suggested that NO inhibition potentiates carrageenan induced hyperalgesia [29]. The role of nitric oxide on analgesic effects of morphine has also been reported. It has been shown that acute administration of l-arginine, the precursor of NO, p.o. or i.p. but not i.c.v. reduces morphine antinociception in mice [30]. Spinal cord NOS inhibition has also enhanced the mu-, delta and kappa opioid receptors-mediated antinociception [31]. Noticeably, the interaction between estrogen and NO system may be responsible for morphine pain perception. It has been well documented that estrogen influences the NO system in both peripheral and nervous tissues [32–34]. It has been shown that estrogen increases eNOS activity and expression [35,36] and production of nitric oxide in endothelial cells [37]. There is evidence showing that estrogen changes nNOS mRNA and the number of nitergic neurons influences NO production in the brain [38,39]. Interaction of both sex hormones and NO with other neurotransmitters such as GABA, acetylcholine, serotonin and dopamine has been widely documented [40–47]. All of these neurotransmitters have some roles in antinociceptive properties of morphine and pain perception [48–56]. Therefore, the aim of the present study was to clarify the different effects of l-NAME (NOS inhibitor) on antinociceptive effects of morphine in male and female rats.

2. Material and methods 2.1. Animals and drugs Male and female Wistar rats (n = 40, 200 ± 20 g) were used. All rats were housed in 4–6 per standard cages, at room temperature (22 ± 1 ◦ C) on a 12 h light/dark cycle. Food and water was available ad libitum. Animal handling and all related procedures were in accordance with approved standards of animal care. The Drugs were l-NAME (Sigma, St Louis, MO, USA) and morphine sulfate (TEMAD Ltd, Teheran, Iran). All drugs were dissolved in saline solution. 2.2. Nociceptive test To assess nociceptive responses, hot plate method was used: rats were placed on the hot plate with temperature setting controlled at 52 ± 0.2 ◦ C. Cut-off time was 80 s. Nociceptive response was defined as licking fore paws or moving

Fig. 1. Comparison of basal reaction times between female and male controls, female-LN and male-LN rat groups. Data are presented as means ± SEM (n = 10 in each group).

hind paws. Time duration between placing the animals on hot plate and licking fore paws or moving hind paws was considered as the reaction time. The hot plate test was performed as a base record 15 min before injection of morphine (10 mg/kg; s.c.) [57] and consequently it was repeated 5 times, every 15 min after injection. 2.3. Experimental design Forty rats were divided into four groups: (1) female; (2) female-LN; (3) male (4) male-LN. The animals of femaleLN and male-LN received l-NAME (10 mg/kg) [58] every day during 3 weeks. The animals of female and male control groups received 2 ml/kg saline instead of l-NAME. Finally, all animals were tested on the hot plate test to evaluate the antinociceptive effects of morphine. 2.4. Statistical analysis All data were presented as means ± SEM of reaction time. Statistical comparison of basal reaction times between groups was done with one-way analysis of variance (ANOVA) and post hoc Tukey test. Repeated measure ANOVA followed by post hoc Tukey test was used for comparison of reaction times after injection of morphine. Differences were considered statistically significant when p < 0.05.

3. Results The basal reaction times were in female and male controls, female-LN and male-LN groups 30.15 ± 1.82, 26.85 ± 2.8, 36.40 ± 1.88 and 30.80 ± 3.1 s, respectively; there were no significant differences between groups (Fig. 1). 30 and 45 min after injection of morphine, the reaction times in male controls were 50.78 ± 6.75 and 55.33 ± 8.18 s, respectively, and were significantly higher than basal reaction time (26.85 ± 2.81 s) (p < 0.05, p < 0.01; Table 1). In female controls, 45 and 60 min after the injection of morphine, the reaction times were 52.08 ± 4.64 and 52.5 ± 6.57 s, respectively, and were significantly higher than the basal reaction

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Table 1 Comparison of reaction times before (basal reaction time) and after injection of morphine (10 mg/kg) in each rat group. Data are presented as mean ± SEM (n = 10 in each group). The animals of both female-LN and male-LN groups were treated by l-NAME (10 mg/kg/day) during 3 weeks. The animals of male and female controls received saline instead of l-NAME. * p < 0.05, ** p < 0.01 and *** p < 0.001 compared to basal reaction time in each group. Groups Male Female Male-LN Female-LN

Base 26.84 30.15 30.8 36.4

± ± ± ±

9.81 1.81 3.09 1.88

15 min 48.25 ± 29.37 ± 23.86 ± 34.82 ±

9.71 3.28 4.02 5.14

30 min 50.77 ± 37.02 ± 39.9 ± 56.74 ±

time (30.15 ± 1.81 s) (p < 0.001; Table 1). Reaction times 60 and 75 min after injection of morphine, were 62.64 ± 8.67 and 62.22 ± 8.29 s, respectively in male-LN group, and were significantly higher than basal reaction times (30.80 ± 3.1 s) (p < 0.01; Table 1). In female-LN group, the reaction times 30, 45, 60 and 75 min after injection of morphine were 56.74 ± 5.37, 69.48 ± 5.98, 64.01 ± 8.74 and 62.79 ± 7.58 s, respectively, and were significantly longer than basal reaction time (36.4 ± 1.88) (p < 0.05 to p < 0.001; Table 1). 15 and 30 min after injection of morphine the reaction times in the male controls was higher than in the female controls (p < 0.01; Fig. 2). Repeated measure ANOVA showed that the reaction times in female-LN group was higher than female controls (p < 0. 01; Fig. 3). There was, however, no significant difference between male and male-LN groups (Fig. 4). Reaction time, 45 min after injection of morphine in femaleLN group was significantly higher male-LN group (p < 0.001; Fig. 5).

6.75* 3.37 6.44 5.37*

45 min 55.33 ± 52.08 ± 39.48 ± 69.48 ±

8.18** 4.64*** 6.94 5.79***

60 min 41.13 ± 52.5 ± 62.64 ± 64.01 ±

6.87 6.57*** 8.67** 8.74***

75 min 41.73 ± 31.32 ± 62.22 ± 62.79 ±

10.15 4.24 8.28** 7.57**

the other hand, role of NO in sex hormone-dependent changes of behavioral responses of female rats has also been reported [63]. We hypothesized that the NO signaling pathway may, at least in part, contribute in difference between male and female rats in morphine-induced antinociception. For this reason, the chronic effect of l-NAME on morphine-induced antinociception in male and female rats was investigated. Hot plate test used in the present study is a well known standard method for pain threshold evaluation after morphine or other analgesic drug administration [64].

4. Discussion Animal and human studies confirm that there is a sexdependent difference in pain and analgesia [3–5,59]. It has been hypothesis that sex differences in opioid antinociception and pain perception are a consequence of actions of female or male gonadal hormones [60–62]. Interactions of both sex hormones and NO with neurotransmitters which are involved in pain modulation have been widely documented [43,44]. On

Fig. 2. Comparison of reaction times after injection of morphine (10 mg/kg) between male and female controls. Data are presented as means ± SEM (n = 10 in each group). 15 and 30 min after injection of morphine the reaction times in male group were higher than female group. ** p < 0.01 compared to female group.

Fig. 3. Comparison of reaction times after injection of morphine (10 mg/kg) between female controls and female-LN group. Data are presented as means ± SEM (n = 10 in each group). Repeated measure ANOVA showed that the reaction times in female-LN group was higher than female controls. The animals of female-LN group were treated by l-NAME (10 mg/kg/day) during 3 weeks.

Fig. 4. Comparison of reaction times after injection of morphine (10 mg/kg) between male and male-LN groups. Data are presented as means ± SEM (n = 10 in each group). There was no significant difference between groups. The animals of male-LN group were treated by l-NAME (10 mg/kg/day) during 3 weeks.

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Fig. 5. Comparison of reaction times after injection of morphine (10 mg/kg) between male-LN and female-LN groups. Data are presented as means ± SEM (n = 10 in each group). 45 min after injection of morphine, the reaction time in female-LN group was significantly higher male-LN group. The animals of both groups were treated by l-NAME (10 mg/kg/day) during 3 weeks. *** p < 0.001 compared to male-LN group.

The results showed no significant differences in baseline hotplate latencies among the male and female rats. This result is in agreement with the study of Negus et al. [65] who reported no difference between female and male animals in sensitivity to thermal stimuli. In another study, Negus and Mello [66] showed that baseline sensitivity to thermal stimuli was similar in male and ovariectomized monkeys. Tall and Crisp [67] showed that the paw withdrawal latency in response to mechanical stimulus is greater in female compared to male rats. In contrast, more sensitivity of female animals to thermal stimuli has also been reported [68]. All of these findings show that sex hormones may have a role in pain perception. However, some reports are controversial. The results of present study also showed that morphine has significantly more effects in male rats in comparison with female rats as the reaction time latencies in male rats were higher than females. Several studies have demonstrated that opioids are generally more potent in producing an antinociception in male than female animals [68–70,60]. This effect may be due to increased sensitivity to mu and kappa antinociception by testostrone [22]. No significant sex difference in fentanyl and buprenorphine antinociceptive effects has been reported by Bartok and Craft [71]. However, other findings have shown that morphine has been approximately twofold more potent in male rhesus monkeys than in ovariectomized females [66]. Therefore, testosterone may not be the only determinant factor. In contrast, it has been demonstrated that pentazonic (kappa-receptor agonist) has produced significantly greater analgesia in female than male animals [72,73]. Decreased ␤-endorphin receptors in hypothalamic, thalamic and midbrain areas by estradiol and progesterone has been reported [74]. Estrogen also decreases the functional coupling of the m-opioid and GABA receptors and suppresses m-opioid and GABA–mediated hyperpolarization of hypothalamic arcuate neurons [75]. High opioid receptor density in hypothalamus during proestrous phase, when estrogen levels are elevated [76] may affect the analgesic function of

opioids. The association of high levels of estrogen with the increased levels of proenkephalin gene expression has also been reported [77]. It has also been shown that estrogen has different regulatory effects in male vs female rats on hypothalamic pre-proenkephalin mRNA [78]. All of these reports as well as the results of present study shows that analgesic effects of morphine are sex-dependent. Nitric oxide (NO) is a gaseous messenger which is produced in different cell types [79]. The diverse distribution of NO imply that it is a potent biological mediator with diverse physiologic functions [80]. Currently it has been documented that NO has a role in pain perception and it has also modulatory function on antinociceptive effects of opioids [31]. NO appears to act as a pronociceptive [81,82] as well as an antinociceptive agent [83]. Our results also demonstrated that chronic treatment by l-NAME affects morphine-induced analgesia; time latency in female-LN group was higher than female group. It has been found that l-NAME dose-dependently inhibited the formalin-induced paw licking in mice [84–86]. There are also controversial reports regarding the role of NO on antinocicpteive effect of morphine and other opioids. Intrathecal administration of l-NAME enhanced morphine antinociception in rats [87]. Xu and Tseng [88] reported that antinociception induced by morphine was increased by injection of N(omega)-nitrol-argnine(l-NNA) (NOS inhibitor) but was attenuated by administrated l-argnine [89]. On the other hand, Pataki and Telegdy [90] reported that l-NNA diminished the morphineinduced analgesia and l-argnine pretreatment potentiated the analgesic effect of morphine. It has been suggested that morphine reduces presynaptic neurotransmitter release such as glutamate, thus lowers the amount of glutamate available for the NMDA receptors. Injection of l-NAME also reduces NO concentrations thus decreases secondarily extracellular concentrations of primary afferent neurotransmitter glutamate. Both of them would lead to attenuation of pain [91]. It has been suggested that inhibition of NO synthase attenuates the NMDA receptor-mediated synaptic transmission of nociception inputs [86] and consequently, it may enhance the opioid antinociception [31]. All of these documents showing that NO has a role in morphineinduced antinociception. The result of present study also showed that l-NAME potentiate the effect of morphine in female but not male rats. The results of present study suggests that NO has different roles in male and female rats. There are other reports showing that the hyperalgesia induced by epinephrine is dependent on sex hormones and NOS inhibition can antagonize the pain only in the male [92]. It has also been reported that pretreatment with l-NAME causes a significant increase in the latency time in hot plate test only in male but not in female mice [1]. Different functions of NO on other pathophysiological conditions in the nervous system have also been reported. Uzüm et al. [93] reported that pretreatment with lNAME completely prevented PTZ-induced seizures in male rats, whereas increased severity, frequency, duration, and sig-

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nificantly shortened the latency in female rats. Unexpectedly, NO donor, sodium nitropruside (SNP) increased convulsion severity, frequency, duration, and shortened latencies in male rats, while the reverse effects were seen in the females. They concluded that sex-dependent differences in seizures severity might be related to NO. All of these data confirm that there are potential levels of interaction between sex hormones and the NO signaling systems in the regulation of antinociceptive effects of morphine.

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Acknowledgment Authors would like to thank the Vice Presidency of Research of Mashhad University of Medical Sciences for financial supports.

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