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1 Laboratório de Endocrinologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21949-900, Brazil2 Departamento de Fisiologia e Farmacologia, Universidade Federal Fluminense, Rio de Janeiro 23070-200, Brazil
(Correspondence should be addressed to C C Pazos-Moura; Email: cpazosm{at}biof.ufrj.br)
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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9-tetrahydrocannabinol (9-THC), has many well-known pharmacological properties. The actions of this phytocannabinoid are mediated by two subtypes of G-protein coupled receptors, CB1 (also known as CNR1) and CB2 (also known as CNR2) (Devane et al. 1988, Matsuda et al. 1990, Munro et al. 1993). CB1 is abundant in the central nervous system, and it is also present in the peripheral nervous system and in several peripheral organs (Tsou et al. 1998). By contrast, CB2 receptor expression in the brain is very low and it is located mostly in immune cells (Klein 2005). Endogenous ligands of cannabinoid receptors were identified and named endocannabinoids (Di Marzo & Fontana 1995). The main endocannabinoids are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, derivates of arachidonic acid, which are produced by the cleavage of membrane lipid precursors (Di Marzo et al. 2004). Endocannabinoids and their receptors together with enzymes for ligand biosynthesis and inactivation comprise the endocannabinoid system (Di Marzo et al. 2004). This system participates in several physiological processes, such as nociceptive transmission, motor activity, learning and memory process, emotional responses, as well as thermoregulation and appetite regulation (Di Marzo et al. 2004, Foster-Schubert & Cummings 2006).
In addition, it has been shown that endocannabinoids have a role in the control of the neuroendocrine system. Anandamide modulates prolactin (PRL) and luteinizing hormone (LH) CGR secretions in a sex steroid-dependent manner. In male rats and female ovariectomized rats, anandamide had the ability to suppress PRL and LH release (Wenger et al. 1995, Scorticati et al. 2003, 2004), while in ovariectomized estrogen-primed rats, it stimulated PRL and LH release (Scorticati et al. 2003, 2004). Regarding growth hormone secretion, one report found that 9-THC administration increased while anandamide decreased the hormone serum concentrations (Wenger et al. 1995). There are also reports that anandamide, centrally injected in rats, was able to increase the secretion of adrenocorticotropin hormone (Weidenfeld et al. 1994).
Earlier reports have demonstrated the ability of a single injection of the phytocannabinoid 9-THC to reduce serum concentrations of TSH and thyroid hormones (Hillard et al. 1984). Another study (Lomax et al. 1970) suggested that the reduction in thyrotropic axis would be consequent to hypothalamic action of 9-THC, resulting in decreased thyrotropin-releasing hormone (TRH) release, although so far, direct evidence is lacking. More recently, it was shown that the synthetic cannabinoid receptor agonist WIN 55212-2 also reduced serum triiodothyronine (T3) and thyroxine (T4), but no alteration was observed on serum TSH (Porcella et al. 2002). Therefore, in the present paper, in order to contribute further insights into the role of the endogenous cannabinoid system on thyrotropic axis function, we investigated the acute effect of anandamide on TSH secretion in vivo and in vitro. We also analyzed the acute effect of a CB1 receptor antagonist, AM251, since CB1 receptors are present at hypothalamus, pituitary, and thyroid glands (Fernandez-Ruiz et al. 1997, Wenger et al. 1999, Porcella et al. 2002, Scorticati et al. 2004).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Adult male Wistar rats, 250–300 g body weight (BW), were kept under a 12 h light:12 h darkness cycle (light onset at 0700 h) at 24±1 °C; a standard diet and tap water were available ad libitum. All experimental protocols were approved by our institutional animal care committee Comissão de Avaliação de Utilização de Animais em Pesquisa (CAUAP) and are in accordance with the FRAME's guidelines. Experiments were performed with eu-, hypo-, and hyperthyroid rats. Hypothyroidism was induced by treatment with 0.03% methimazole (Sigma) in the drinking water for 21 days. Hyperthyroidism was induced by s.c. daily single injection of T4 (L-Thyroxine Sigma), 10 µg/100 g BW for 6 days.
In vivo experiments
Systemic administration of anandamide or AM251, a selective CB1 receptor antagonist Euthyroid animals were divided into four groups that received a single i.p. injection of vehicle (propylene glycol:ethanol:saline 1:1:2 – control) or 0.02 mg/kg BW anandamide (Tocris Cookson Inc., Ellisville, MO, USA) and killed by decapitation 0.5, 1, or 2 h after the injection. Control group was killed at a time between 1 and 2 h. Other group of euthyroid rats received a single i.p. administration of vehicle or 0.2 mg/kg BW anandamide and killed 2 h later. Drug administration protocol was based on that employed by Wenger et al. (1997) who demonstrated that 0.02 mg/kg BW anandamide stimulated the secretion of adrenocorticotropic hormone (ACTH) and corticosterone in rats.
Hypo- and hyperthyroid animals were divided into two groups that received a single i.p. injection of vehicle (control) or 0.02 mg/kg BW anandamide, and killed 2 h later. The time was chosen based on the results observed on euthyroid animals.
In order to evaluate the response of the thyroid axis to selective CB1 receptor antagonist/inverse agonist, AM251, euthyroid animals were injected i.p. with vehicle (3% DMSO), 0.17 mg/kg or 1.7 mg/kg BW of AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (Tocris Cookson Inc.), and killed 1.5 h later. AM251 dose was chosen based on previous reports on behavior studies that had injected rats with the drug intraperitoneally (Chambers et al. 2004, McLaughlin et al. 2005, Xi et al. 2006).
In order to investigate the involvement of endocannabinoid receptors on the effect of anandamide on the thyrotropic axis, 0.17 mg/kg BW AM251 was injected 30 min before the administration of 0.02 mg/kg anandamide in euthyroid rats, and compared with groups treated with 0.02 mg/kg anandamide alone or 0.17 mg/kg BW AM251 alone. To serve as a control group, half of the animals were injected with AM251 vehicle and other half with anandamide vehicle, and since data of these two groups did not differ, they were pooled and presented together. Animals were killed 2 h after anandamide injection.
In all experiments, animals were killed by decapitation and serum was obtained from trunk blood to measure TSH and total T4 and T3 concentrations. Experiments were performed until 1100 h, in order to avoid circadian fluctuations interfering with results.
Central administration of anandamide
Rats underwent third ventricular cannulation (i.c.v.) 7 days before the experiment. A stainless steel guide cannula (0.6 mm o.d.) for microinjection was implanted 0.5 mm posterior to bregma and 8.0–8.5 mm ventral to the skull, as reported before (Antunes-Rodrigues & McCann 1970, Rettori et al. 1992), under ketamine plus xylazine anesthesia. Verification of correct cannula placement was made by the observation of fluid-filled column (attached to guide cannula) displacement. The day before the experiment, a jugular catheter was implanted, under the same anesthetic protocol described above. Briefly, the jugular vein was isolated by blunt dissection and a catheter made of silastic tubing was introduced about 2.2 mm down. The free end of the catheter was passed under the skin and externalized between the scapulae. The catheter was flushed with heparin saline (50 U/ml). The next morning, extension tubing was attached to the jugular catheter and animals were left undisturbed for half an hour, then a basal heparinized blood sample was collected, followed by the i.c.v. injection of a solution of 20 or 200 ng anandamide in 2 µl or an equal volume of vehicle (Trocrisolve, Tocris Cookson Inc). Blood samples were collected 30, 60, and 120 min after microinjection. After each sample collection, volume replacement was conducted with sterile saline.
In vitro experiments: pituitary explants
The in vitro protocol was performed as described previously (Rettori et al. 1989, 1992, Pazos-Moura et al. 1996, Ortiga-Carvalho et al. 2002). Euthyroid animals were killed by decapitation and their anterior pituitaries were quickly dissected. Each hemi-pituitary was immediately transferred to a flask containing 1 ml Krebs–Ringer bicarbonate medium (pH 7.4) at 37 °C in an atmosphere of 95% O2:5% CO2 in a Dubnoff metabolic shaker. After a 30-min preincubation period, medium was changed and glands were incubated in the absence or presence of tested drugs. In the first experiment, glands were incubated with 10–11, 10–9, or 10–7 M anandamide in Tocrisolve (Tocris Cookson Inc). In the second experiment, glands were incubated with anandamide or AM251 or both drugs at the same molarity (10–7 M). At the end of 2-h incubation an aliquot was removed, and kept at –20 °C until assayed for TSH measurement.
Hormone measurements
TSH concentrations in serum and in incubation medium were measured by specific RIA, employing reagents supplied by National Hormone and Peptide Program (Torrance, CA, USA), as previously described (Chard 1987, Ortiga-Carvalho et al. 1996), and it was expressed in terms of the reference preparation (RP3). The assay is highly specific for rat TSH and no significant cross-reactivity is reported by the supplier. Minimum assay detection value was 0.18 ng/ml and within-assay variation was less than 8% in all assays. Total serum T4 and T3 was detected by RIA (Total T4 or Total T3 Mab-ICN Pharmaceuticals, Costa Mesa, CA, USA). Minimum assay detection value was 25 ng/dl for T3, 1 µg/dl for T4, and within-assay variation was less than 4.5% for T3 and less than 3.5% for T4 in all assays. Samples of the same experiment were run within the same assay.
Statistical analyses
Data are reported as mean±S.E.M. Serum TSH was analyzed employing Kruskal–Wallis test followed by Dunn's multiple comparison test or Mann–Whitney test, in experiments with two experimental groups. One-way ANOVA followed by Dunnett's multiple comparison test was employed for an assessment of the significance of in vitro TSH. T4 and T3 data were analyzed by ANOVA or unpaired t-test, according to the number of experimental groups (Zar 1996). Null hypothesis was discarded when P<0.05.
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Results |
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In euthyroid rats (Fig. 1A), serum TSH was decreased by 
42% in animals that had received, 2 h earlier, a single systemic injection of 0.02 mg/kg BW anandamide (P<0.05). At the same time interval, serum T4 showed a 39% reduction (P<0.01; Fig. 1B). At earlier time-points (0.5 and 1 h), anandamide had no significant effect on serum TSH or serum T4. Serum T3 was statistically similar among all groups (Fig. 1B). However, a ten-time higher anandamide dose (0.2 mg/kg) had no effect on serum TSH, T4, and T3 (Fig. 2).
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35% in serum TSH was observed (P<0.01; Fig. 3A), but there was no change in serum thyroid hormones concentrations (Fig. 3B).
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Acute effect of CB1 receptor antagonist AM251 on thyrotropin secretion of euthyroid rats
As depicted in Fig. 4A, a single injection of AM251, injected 1.5 h before killing, induced a dose increase in serum TSH, of 1.7 (P<0.05) or 4.3 times (P<0.001) in animals receiving 0.17 or 1.7 mg/kg BW AM251 respectively (Fig. 4B). However, no statistically significant effects were observed regarding serum T4 and T3.
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Figure 5 shows that the inhibitory effect of 0.02 mg/kg BW anandamide and the stimulatory effect of 0.17 mg/kg BW AM251 were abolished in rats receiving AM251 30 min before the injection of anandamide. The latter group presented serum TSH statistically similar to control group. All animals were killed 2 h after anandamide injection.
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Serum TSH was evaluated before and at 30, 60, and 120 min after injection into the third ventricle of 20 or 200 ng anandamide. Figure 6 shows the variation of serum TSH in relation to basal levels (before injection). At 30 min, anandamide injection, at both doses, caused no significant change in TSH secretion. At 60 min, anandamide at 20 ng induced a significant reduction in TSH secretion (P<0.05). The same trend was observed with 200 ng anandamide; however, the variation in serum TSH was not statistically significant. One hour later (at 120 min after microinjection), no significant effect was observed, although only the group treated with 20 ng anandamide still had a trend to reduce TSH secretion.
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The presence of anandamide in incubation media of hemi-pituitary glands showed a dose-related effect on TSH released to the medium. At 10–11 M, release of TSH was increased (1.6 times, P<0.05); however, at 10–7 M, there was a significant reduction (66%), while the intermediary dose (10–9 M) induced no significant change in secretion (Fig. 7A). In the second experiment, we observed that the inhibitory effect of 10–7 M anandamide in TSH release was blocked by the CB1 receptor antagonist AM251 at 10–7 M (P<0.05; Fig. 7B). The incubation with 10–7 M AM251 alone showed a non-statistically significant trend to increase TSH release in comparison with control and a significant increase in relation to anandamide-treated group (P<0.05), which showed a 30% decrease in relation to control (P<0.05; Fig. 7B).
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Discussion |
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The inhibitory effect of anandamide on TSH secretion occurred 2 h after systemic injection and was accompanied by concomitant reduction in serum T4. These data suggest that anandamide acts at the pituitary and/or hypothalamus in order to inhibit TSH secretion, since increased TSH would be expected if the only site of action was the thyroid. An earlier study showed that the phytocannabinoid 9-THC was able to reduce serum TSH from 15 min to 3 h after a single i.p. injection, followed by a decrease in serum T3 and T4 at 3 and 6 h respectively (Hillard et al. 1984). However, in our study, the reduction in serum TSH and T4 was concomitant and, considering the long half-life of serum T4, unless TSH bioactivity was reduced at a much earlier time, it is likely that anandamide was also acting at the thyroid gland. In support to a direct action in the thyroid, there was the previous report by Porcella et al. (2002), showing that 4 h after the injection of cannabinoid receptor agonist WIN 55212-2, serum thyroid hormones were reduced without changes in serum TSH. This effect of the agonist was abolished by pre-treatment with specific CB1 antagonist SR 141716A. However, it is not clear which subtype of cannabinoid receptor mediates the effect of WIN 55212-2, on thyroid, since, so far, only CB1 was found in the thyroid (Porcella et al. 2002), and WIN 55212-2 is a CB2 preferring agonist.
Further evidence of the central action of anandamide was obtained by the demonstration of the inhibitory anandamide effect of on TSH secretion, without changes in serum thyroid hormones, in rats treated with methimazol, a drug that inhibits thyroid hormone biosynthesis. In addition, the fact that anandamide preserves its ability to reduce serum TSH in hypothyroid state highlights the potency of endocannabinoid effect on TSH regulation, since lack of thyroid hormones is a major determinant of high serum TSH (Weintraub et al. 2001). However, apparently, anandamide was not able to further decrease the already suppressed TSH serum concentrations of hyperthyroid rats.
The involvement of CB1 receptors in the control of TSH release is suggested by the acute rise in serum TSH induced by AM251 and by the fact that AM251 pre-treatment prevented anandamide effect. AM251 stimulatory effect on TSH release may be interpreted as that of anandamide, which acts preferentially by CB1 receptors, having a tonic inhibitory effect that is blocked by the CB1 receptor antagonist. Another likely explanation would be that AM251, acting as an inverse agonist, reduces the CB1 receptor signaling transduction pathway (Pertwee 2005). AM251, injected into the third cerebral ventricle, had been reported to change LH and PRL secretions in the opposite direction to anandamide effects (Scorticati et al. 2003, 2004). Serum thyroid hormones did not change in response to the rise in TSH induced by AM251, which may be related to the short time observed after the drug administration (1.5 h) or to the biological potency of the amount of TSH secreted. In a previous study (Porcella et al. 2002), systemic injection of CB1 receptor antagonist SR141716A did not modify serum TSH, T3, or T4. However, hormonal evaluation was performed 4 h after injection, while we used an earlier time in the current study. Therefore, it remains to be elucidated whether these different reports are related to time-course or to particularities attributed to each drug.
CB1 receptors have been demonstrated, albeit in low density, in hypothalamic nuclei (Fernandez-Ruiz et al. 1997, Scorticati et al. 2004) and also CB1-like immunoreactivity was found in rat and human anterior pituitaries (Fernandez-Ruiz et al. 1997, Pagotto et al. 2001, Scorticati et al. 2004). Therefore, the in vivo effect of anandamide on TSH release may result from a direct action at pituitary and/or hypothalamus. The possibility of a direct hypothalamic action is reinforced by the inhibitory effect we observed within 60 min after the i.c.v. administration of 20 ng anandamide. Wenger et al. (1997) had used a systemic treatment regimen identical to that employed in the present study and demonstrated that anandamide increased POMC release in concomitance with proto-oncogene protein c-fos (FOS) activation in paraventricular nucleus (PVN) hypothalamic neurons, peaking at 90 min after anandamide injection. Therefore, the time-course of our results is in accordance with a postulated action at hypothalamic site. In addition, earlier studies had shown that the phytocannabinoid 9-THC was not able to acutely affect serum TSH in animals with electrolytic lesions in medial mammillary nuclei of the hypothalamus (Lomax et al. 1970). Regarding systemic administration of AM251, a hypothalamic site of action is also possible, since previous studies have shown that following i.v. injection of [123 I]AM251 in mice, the peak whole-brain uptake of about 1% of the administered activity occurred at about 1 h and declined thereafter (Gatley et al. 1996). In addition, there are reports of centrally mediated effects induced by systemic acute administration of AM251, employed in the same dose range of our higher dose, such as a decrease in food ingestion behavior (Chambers et al. 2004) and inhibition of cocaine-induced reinstatement of reward-seeking behavior (Xi et al. 2006).
The precise mechanism by which endogenous cannabinoid may modify TSH release cannot be elucidated by the present study. Considering the short half-life of anandamide and the relative long latency for the anandamide central effect on serum TSH, it is possible that this endocannabinoid did not act directly on TRH neurons, but likely that other mechanisms are involved (de Miguel et al. 1998, Scorticati et al. 2003). Scorticati et al. (2003) reported that dopamine concentration in medial basal hypothalamus and anterior pituitary was increased 90 min after a single intracerebroventricular injection of anandamide, which concomitantly induced inhibition of PRL release (Scorticati et al. 2003). Since dopamine is an inhibitor of PRL and TSH (Weintraub et al. 2001), a mechanism by which anandamide may inhibit PRL and also TSH release is via increasing dopamine input.
However, endocannabinoids may also modulate TSH secretion by a direct pituitary action. We were able to demonstrate the ability of anandamide at 10–7 M to reduce TSH release, an effect at least in part mediated by cannabinoid receptor 1, since it was blocked by AM251. However, anandamide at lower molarity (10–11 M) provoked an increase in TSH secretion to medium, and therefore the pituitary action of endogenous cannabinoid may vary depending on the concentration present in the gland.
Interestingly, a ten-time higher dose of anandamide, injected systemically or centrally, was not able to affect the thyrotropic axis. There are many reports showing lower biological efficacy of endogenous substances administered at higher dose than lower doses, including anandamide (Ortiga-Carvalho et al. 2002, Fernandez-Solari et al. 2004, Scorticati et al. 2004, Oliveira et al. 2006).
Thyroid hormones and endocannabinoids participate in energy homeostasis in opposite directions; while thyroid hormones are major stimulants of the basal metabolic rate and energy expenditure, endocannabinoids are important stimulators of food ingestion and energy conservation. During starvation, thyrotropic axis activity is reduced (Weintraub et al. 2001), while endocannabinoid levels increase (Matias & Di Marzo 2007). Therefore, it seems feasible to the existence of a physiologically relevant negative regulation of thyrotropic axis by endocannabinoids. In addition, since CB1 receptor antagonists are currently being introduced in therapeutics (Di Marzo et al. 2004), it will be important to investigate the consequences to pituitary–thyroid axis of chronic administration of CB1-receptors antagonists.
In conclusion, anandamide, an endogenous cannabinoid, has the ability to acutely inhibit TSH release in eu- and hypothyroid rats, acting at the hypothalamus–pituitary axis. Since the cannabinoid receptor antagonist, AM251, increased TSH release in vivo and blocked the effect of anandamide, it is suggested that endocannabinoid system may play a role as a negative regulator of TSH secretion in vivo.
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Declaration of interest |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Funding |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Received in final form 20 August 2008
Accepted 27 August 2008
Made available online as an Accepted Preprint 28 August 2008
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