ArticleLiterature Review

The role of endocannabinoids in the hypothalamic regulation of visceral function

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Abstract

The hypothalamus plays an important role in the regulation of several visceral processes, including food intake, thermoregulation and control of anterior pituitary secretion. Endogenous cannabinoids and CB(1) cannabinoid receptors have been found in the hypothalamus. In the present review, we would like to clarify the role of the endocannabinoid system in the regulation of the above-mentioned visceral functions. There is historical support for the role of marihuana (i.e. exogenous cannabinoids) in the regulation of appetite. Endocannabinoids also stimulate food intake. Furthermore, the specific CB(1) receptor antagonist SR141716 reduces food intake. Leptin treatment decreases endocannabinoid levels in normal rats and ob/ob mice. These findings provide evidence for the role of the hypothalamic endocannabinoid system in food intake and appetite regulation. Cannabinoids can change body temperature in a dose-dependent manner. High doses cause hypothermia while low doses cause hyperthermia. Cannabinoid administration decreases heat production. It seems that the effects of can- nabinoids on thermoregulation is exerted by altering some neurochemical mediator effects at both the presynaptic and postsynaptic level.THC and endocannabinoids have mainly inhibitory effects on the regulation of reproduction. Administration of anandamide (AEA) decreases serum luteinizing hormone (LH) and prolactin (PRL) levels. AEA causes a prolongation of pregnancy in rats and temporarily inhibits the postnatal development of the hypothalamo-pituitary axis in offspring. The action of AEA on the reproductory parameters occurs at both the hypothalamic and pituitary level. CB(1) receptors have also been found in the anterior pituitary. Further, LH levels in CB(1) receptor-inactivated mice were decreased compared with wild-type mice. Taken together, all these observations suggest that the endocannabinoid system is playing an important part in the regulation of the mentioned visceral functions and it provides the bases for further applications of cannabinoid receptor agonists and/or antagonists in visceral diseases regulated by the hypothalamus.

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... Over the past centuries, Cannabis sativa (D9-tetrahydrocannabinol) has been used extensively for both medicinal and recreational uses [72]. The search for the endogenous receptor for the psychoactive component of Cannabis sativa has led to the discovery of physiological endocannabinoids [anandamide, 2-arachidonoylglycerol (2-AG), noladin ether, NADA, and virodhamine] and physiological ''cannabinoid'' signaling system that acts on at least 2 receptors: CB1 and CB2 [73][74]. These receptors are located not only in pleasure centres of CNS, but also in many organs associated with feeding and energy regulation, such as the hypothalamus and the gastrointestinal tract [74]. ...
... The search for the endogenous receptor for the psychoactive component of Cannabis sativa has led to the discovery of physiological endocannabinoids [anandamide, 2-arachidonoylglycerol (2-AG), noladin ether, NADA, and virodhamine] and physiological ''cannabinoid'' signaling system that acts on at least 2 receptors: CB1 and CB2 [73][74]. These receptors are located not only in pleasure centres of CNS, but also in many organs associated with feeding and energy regulation, such as the hypothalamus and the gastrointestinal tract [74]. In a number of species, including humans, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. ...
... Thus, leptin administration, which exerts an anorectic action, suppresses hypothalamic endocannabinoid levels in normal rats, while genetically obese, chronically hyperphagic rats and mice express elevated leptin-reversible, hypothalamic anandamide or 2-AG levels [75]. These findings provide evidence for the role of the hypothalamic endocannabinoid system in food intake and appetite regulation [74]. Experiments with selective CB1 receptor antagonists (e.g. ...
Article
The growing worldwide prevalence of obesity needs urgent attention because the potential morbidity, mortality, and economic tolls have to be avoided. Despite obesity is known as a healthcare issue on an epidemic scale, it remains largely an unsolved medical problem. The successful management of obesity is theoretically possible through lifestyle changes, with diet modifications and increasing physical activity. However, low results by traditional treatments have inevitably prompted interest in the development of effective therapies, including pharmacological interventions and gastrointestinal surgery. As our knowledge of the physiological systems regulating food intake and body weight has considerably increased over the past decade, many studies have underlined the scientific and clinical relevance of potential treatments based on peripheral hormones or central neuropeptides signals. Here we have summarized the complex pattern of the appetite regulation, divided into central and peripheral mechanisms. In the second part of this paper, we have reviewed the currently approved and putative obesity therapies. Up to now only two drugs, sibutramine and orlistat have been approved by the Food and Drug Administration for long term use, but several other medications are currently used to cure severe obesity and many other are developing. Thus, in the last part, we have analyzed recent literature and patents describing new and upcoming molecules. The new anti-obesity drugs under clinical development include agents affecting peripheral and central mechanisms. Further investigations are needed to approve these upcoming therapeutic agents for the treatment of obesity.
... As mentioned in the preceding text, classic cannabinoids, such as ∆ 9 -THC, and also endogenous cannabinoids, such as anandamide, decreased the release of most of anterior pituitary hormones, including prolactin (Rettori et al., 1988;Romero et al., 1994;Wenger et al., 1994;Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), luteinizing hormone (Murphy et al., 1990(Murphy et al., , 1994Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), growth hormone (Rettori et al., 1988; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), thyrotropin (Hillard et al., 1984; for a review, see Murphy et al., 1998), and, to a lesser extent, follicle-stimulating hormone (Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for a review, see Murphy et al., 1998;Wenger and Moldrich, 2002), with the only exception of corticotrophin, which was stimulated by cannabinoids ; for a review, see Murphy et al., 1998). This occurred mainly in male animals, the effects in females being slightly different and depending on the ovarian cycle (Bonnin et al., 1993;Rodríguez de Fonseca et al., 1994;Scorticati et al., 2003). ...
... As mentioned in the preceding text, classic cannabinoids, such as ∆ 9 -THC, and also endogenous cannabinoids, such as anandamide, decreased the release of most of anterior pituitary hormones, including prolactin (Rettori et al., 1988;Romero et al., 1994;Wenger et al., 1994;Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), luteinizing hormone (Murphy et al., 1990(Murphy et al., , 1994Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), growth hormone (Rettori et al., 1988; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), thyrotropin (Hillard et al., 1984; for a review, see Murphy et al., 1998), and, to a lesser extent, follicle-stimulating hormone (Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for a review, see Murphy et al., 1998;Wenger and Moldrich, 2002), with the only exception of corticotrophin, which was stimulated by cannabinoids ; for a review, see Murphy et al., 1998). This occurred mainly in male animals, the effects in females being slightly different and depending on the ovarian cycle (Bonnin et al., 1993;Rodríguez de Fonseca et al., 1994;Scorticati et al., 2003). ...
... As mentioned in the preceding text, classic cannabinoids, such as ∆ 9 -THC, and also endogenous cannabinoids, such as anandamide, decreased the release of most of anterior pituitary hormones, including prolactin (Rettori et al., 1988;Romero et al., 1994;Wenger et al., 1994;Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), luteinizing hormone (Murphy et al., 1990(Murphy et al., , 1994Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), growth hormone (Rettori et al., 1988; for reviews, see Murphy et al., 1998;Wenger and Moldrich, 2002), thyrotropin (Hillard et al., 1984; for a review, see Murphy et al., 1998), and, to a lesser extent, follicle-stimulating hormone (Fernández-Ruiz et al., 1997;de Miguel et al., 1998; for a review, see Murphy et al., 1998;Wenger and Moldrich, 2002), with the only exception of corticotrophin, which was stimulated by cannabinoids ; for a review, see Murphy et al., 1998). This occurred mainly in male animals, the effects in females being slightly different and depending on the ovarian cycle (Bonnin et al., 1993;Rodríguez de Fonseca et al., 1994;Scorticati et al., 2003). ...
... In the central nervous system, the actions of endocannabinoids are primarily exerted via the type-1 cannabinoid receptor (CB1), located in the axon terminals [39]. Cannabinoid receptor-expressing neurons, including GABAergic neurons [40], have their cell bodies in the hypothalamus [41,42]. Several studies have shown that endocannabinoids can modulate neurotransmitter action and release [9,10]. ...
... Several studies have shown that endocannabinoids can modulate neurotransmitter action and release [9,10]. Electrophysiological and immunohistochemical studies show that binding of endocannabinoids to their receptors activates a retrograde action to inhibit GABAergic input onto GnRH neurons [42]. Additionally, GABAA receptors (that can be excitatory) are co-localized with GnRH neurons in the hypothalamus [43]. ...
Article
Full-text available
Stress is known to be an inhibitor of the reproductive hypothalamic-pituitary-gonadal (HPG) axis. However, the neural and molecular connections between stress and reproduction are not yet understood. It is well established that in both humans and rodents, kisspeptin (encoded by the kiss1 gene) is a strong stimulator of the HPG axis. In the present study we hypothesized that endocannabinoids, an important neuromodulatory system in the brain, can act on the HPG axis at the level of kiss1 expression to inhibit reproductive function under stress. Adult male Wistar rats were unilaterally implanted with an intracerebroventricular cannula. Afterwards, the animals were exposed to immobilization stress, with or without the presence of the cannabinoid CB1 receptor antagonist AM251 (1 µg/rat). Blood samples were collected through a retro-orbital plexus puncture before and after stress. Five hours after the stress, brain tissue was collected for reverse transcriptase-quantitative polymerase chain reaction measurements of kiss1 mRNA. Immobilization stress (1 hour) resulted in a decrease in the serum luteinizing hormone concentration. Additionally, kiss1 gene expression was decreased in key hypothalamic nuclei that regulate gonadotrophin secretion, the medial preoptic area (mPOA), and to some extent the arcuate nucleus (ARC). A single central administration of AM251 was effective in blocking these inhibitory responses. These findings suggest that endocannabinoids mediate, at least in part, immobilization stress-induced inhibition of the reproductive system. Our data suggest that the connection between immobilization stress and the HPG axis is kiss1 expression in the mPOA rather than the ARC.
... This finding was surprising, as previous results showed that SR1 pretreatment attenuated the CS response [42]. Furthermore, CB1 receptors have been shown to be involved in the drug-induced suppression by other hormones, such as luteinizing hormone, prolactin, and testosterone [34,45], and these receptors have also been demonstrated in the hypothalamus and the anterior pituitary [45]. However, it is noteworthy that CB1 protein was reported to be most prominent in lactotroph cells and luteinizing hormone-secreting gonadotrophs in the pituitary and less pronounced in corticotroph cells [46]. ...
... This finding was surprising, as previous results showed that SR1 pretreatment attenuated the CS response [42]. Furthermore, CB1 receptors have been shown to be involved in the drug-induced suppression by other hormones, such as luteinizing hormone, prolactin, and testosterone [34,45], and these receptors have also been demonstrated in the hypothalamus and the anterior pituitary [45]. However, it is noteworthy that CB1 protein was reported to be most prominent in lactotroph cells and luteinizing hormone-secreting gonadotrophs in the pituitary and less pronounced in corticotroph cells [46]. ...
Article
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T helper cell type 1 (Th1)-polarizing cytokines are induced by Legionella pneumophila infection and are suppressed by pretreatment with marijuana cannabinoids (CB). Glucocorticoids and prostaglandin E2(PGE2) are also reported to suppress Th1 polarization and are induced by Delta9-tetrahydrocannabinol (THC), so their role in the suppression of polarizing cytokines was examined. Injection of L. pneumophila or THC alone into BALB/c mice induced a rapid and transient rise in serum corticosterone (CS), and the injection of both agents significantly augmented the CS response, demonstrating that THC increased CS in Legionella-infected mice. Pretreatment with the CB receptor 1 (CB1) antagonist SR141716A had no effect on the THC-induced CS response, but CB2 antagonist (SR144528) treatment increased the CS response. To see if increased CS contributed to the down-regulation of Th1 cytokines, mice were pretreated with the steroid antagonist RU486 before THC injection and Legionella infection. The results showed that RU486 did not attenuate the THC-induced suppression of serum interleukin (IL)-12 or interferon-gamma (IFN-gamma). In addition to CS, THC injection increased urinary PGE2 metabolites, and the CB1 antagonist attenuated this increase. Although L. pneumophila infection increased urinary PGE2, THC pretreatment did not enhance this response; in addition, treatment with the cyclooxygenase inhibitor, indomethacin, did not block the THC-induced suppression of IL-12 and IFN-gamma. These results suggest that the elevation of CS and PGE2 does not account for the THC-induced attenuation of the Th1 cytokine response, and it is concluded that other suppressive mediators are induced by THC or that the drug acts directly on immune cells to suppress cytokine production.
... For instance, GABA reuptake inhibition by NO-328 (i.e., tiagabine) augmented the catalepsy (but not the antinociception or hypothermia) produced by Δ 9 -THC in rodents, (Pertwee et al., 1988Pertwee et al., , 1991). Likewise, individual studies have shown that under certain conditions, CB agonists and GABA transporter blockers are anxiolytic (Moreira and Wotjak, 2010; Schmitt and Hiemke, 1999), induce hypothermia (Frosini et al., 2004; Wenger and Moldrich, 2002), impair memory processes and motor activity (Castellano et al., 2003; Sañudo-Peña et al., 2000; Schmitt and Hiemke, 2002; Suzdak et al., 1992), and produce antinociception (Hohmann, 2002; Laughlin et al., 2002). Furthermore, in separate clinical studies, CB agonists and tiagabine have each been shown to alleviate pain and anxiety (Bestard and Toth, 2011; Glass et al., 1980; Karst et al., 2010; Nakano et al., 1978; Schwartz and Nihalani, 2006; Zwanzger et al., 2003). ...
Article
The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ(9)-THC using more pharmacologically specific drug-discrimination procedures. Eight cannabis users learned to discriminate 30 mg oral Δ(9)-THC from placebo and then received tiagabine (6 and 12 mg), Δ(9)-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ(9)-THC produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on psychomotor performance tasks. The higher tiagabine dose substituted for the Δ(9)-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ(9)-THC when administered alone. In combination, tiagabine shifted the discriminative-stimulus effects of Δ(9)-THC leftward/upward and enhanced Δ(9)-THC effects on other outcomes. These results indicate that GABA is involved in the clinical effects of Δ(9)-THC, and by extension, cannabis. Future studies should test selective GABAergic compounds to determine which receptor subtype(s) are responsible for the effects observed when combined with cannabinoids.
... In addition, baclofen augmented the catalepsy produced by Δ 9 -THC in rodents (Pertwee et al., 1988). Preclinical studies that have tested cannabinoid and GABA B agonists separately have demonstrated overlap in their pharmacological profiles; specifically, these drugs are anxiolytic (Moreira and Wotjak, 2010;Pilc and Nowak, 2005), induce hypothermia (Frosini et al., 2004;Wenger and Moldrich, 2002), impair memory processes (Castellano et al., 2003;DeSousa et al., 1994), and produce peripheral antinociception (Dario et al., 2007;Hohmann, 2002). ...
Article
Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ(9)-THC. The aim of the present study was to determine the potential involvement of the GABA(B) receptor subtype by assessing the separate and combined effects of the GABA(B)-selective agonist baclofen and Δ(9)-THC using pharmacologically specific drug-discrimination procedures. Eight cannabis users learned to discriminate 30mg oral Δ(9)-THC from placebo and then received baclofen (25 and 50mg), Δ(9)-THC (5, 15 and 30mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ(9)-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50mg) substituted for the Δ(9)-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ(9)-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ(9)-THC-like subjective responses when administered alone. These results suggest that the GABA(B) receptor subtype is involved in the abuse-related effects of Δ(9)-THC, and that GABA(B) receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABA(A)) to determine the contribution of the different GABA receptors in the effects of Δ(9)-THC, and by extension cannabis, in humans.
... Interestingly in autoradiographic assays of the CNS, to determine the location and concentration of CB 1 receptors, it was found that some places in the CNS that were associated with effects that cannabinoids produce, did not have a high concentration of receptors but had very tight G protein-coupling (Freund et al. 2003). For example, CB 1 receptors are not highly concentrated in the hypothalamus, yet the hypothalamus is affected by cannabinoids and produces the hypothermia and hunger seen when cannabinoids are consumed in humans (Wenger and Moldrich 2002). The spinal cord and brain stem are other examples of tissues with lower concentrations of CB 1 receptors yet produce significant responses when exposed to cannabinoids such as blood pressure changes and anti-emetic effects associated with the brain stem being affected, and analgesia and anti-hypernociceptive effects associated with the spinal cord (Malinowska et al. 2012;Manzanares et al. 2006). ...
... 18,19 These receptors mediate the effects of cannabinoids by reducing the release of anterior pituitary hormones (prolactin, gonadotropin, growth hormone) and increasing corticotropin secretions. 20 Disturbances of the hypothalamic-pituitary-adrenal axis and the presence of autonomic instability have been described as the framework for symptoms in those with CVS. 21 Taché 21 also characterized the increased secretion and activation of corticotropinreleasing factor in the development of CVS. ...
Article
To promote wider recognition and further understanding of cannabinoid hyperemesis (CH). We constructed a case series, the largest to date, of patients diagnosed with CH at our institution. Inclusion criteria were determined by reviewing all PubMed indexed journals with case reports and case series on CH. The institution's electronic medical record was searched from January 1, 2005, through June 15, 2010. Patients were included if there was a history of recurrent vomiting with no other explanation for symptoms and if cannabis use preceded symptom onset. Of 1571 patients identified, 98 patients (6%) met inclusion criteria. All 98 patients were younger than 50 years of age. Among the 37 patients in whom duration of cannabis use was available, most (25 [68%]) reported using cannabis for more than 2 years before symptom onset, and 71 of 75 patients (95%) in whom frequency of use was available used cannabis more than once weekly. Eighty-four patients (86%) reported abdominal pain. The effect of hot water bathing was documented in 57 patients (58%), and 52 (91%) of these patients reported relief of symptoms with hot showers or baths. Follow-up was available in only 10 patients (10%). Of those 10, 7 (70%) stopped using cannabis and 6 of these 7 (86%) noted complete resolution of their symptoms. Cannabinoid hyperemesis should be considered in younger patients with long-term cannabis use and recurrent nausea, vomiting, and abdominal pain. On the basis of our findings in this large series of patients, we propose major and supportive criteria for the diagnosis of CH.
... This implies that Abcb1a/b (2/2) and Abcg2 (2/2) mice could also be more sensitive to CNS-mediated functional effects of THC. It is well established that THC promotes hypothermia through its action on the CNS largely by affecting thermoregulatory neurons in the hypothalamus [35]. For example, a classic study by Fitton and Pertwee (1982) demonstrated that intracerebroventricular and intrahypothalamic injections of THC promoted reductions in rectal body temperature in mice [36]. ...
Article
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The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ(9)-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (-/-), Abcg2 (-/-) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (-/-) and Abcg2 (-/-) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (-/-) mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis.
... Näissä eläinkokeissa rimonabantti esti LH-ja prolaktiinipitoisuuksien pienenemisen. Toisessa tutkimuksessa havaittu pieni LH-pitoisuus hiirillä, joilta on poistettu CB 1 -reseptorigeeni viittaa myös siihen, että CB 1 -reseptorin aktivaatio on tarpeellinen lisääntymistoimintojen säätelyssä (Wenger ja Moldrich 2002). ...
Article
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Arabilääkärit käyttivät marihuanaa (Cannabis sativa) kuumelääkkeenä jo tuhat vuotta sitten. Joissakin länsimaissa kannabista käytetään kipulääkkeenä ja estämään AIDS-poti-laiden laihtumista. Marihuanan vaikuttavien aineiden tutkimus on johtanut kannabinoi-direseptorien ja lopulta kokonaisen uuden välittäjäaineryhmän, endokannabinoidien löy-tymiseen. Nämä elimistön omat välittäjäaineet ovat bioaktiivisia lipidejä, monityydytty-mättömien rasvahappojen johdoksia, jotka vaikuttavat mm. syömis-ja juomiskäyttäyty-miseen sekä unen säätelyyn. Endokannabinoideilla on merkitystä neuromodulaattoreina muun muassa keuhkoputkien ja verisuonten tonuksen, apoptoosin, kipu-ja mielihyväko-kemuksen sekä oppimisen ja muistin säätelyssä. M arihuanan pääasiallisen vaikuttavan ai-neen tetrahydrokannabinolin (THC) ak-tivoiman kannabinoidireseptorin (CB 1 -reseptori) löytyminen johti näihin reseptoreihin vaikuttavien lääkeaineiden kehittelyyn ja endo-geenisten agonistien, endokannabinoidien löy-tymiseen (Matsuda ym. 1990, Felder ym. 1993). CB 1 -reseptorit sijaitsevat presynaptisten hermo-solujen pinnalla ja ovat yhteydessä sytoplasman puolella solun signaalinvälitykseen keskeisesti osallistuvaan G-proteiiniin (Basavarajappa ja Hungund 2002; Rueda ym. 2002). Näitä resep-toreita on usealla alueella keskushermostossa, kuten aivokuoressa, hippokampuksessa, tyvitu-makkeissa ja pikkuaivoissa. Tämä jakauma so-pii yhteen kannabinoidien vaikutuksiin, jotka kohdistuvat muistiin, kognitioon, kivun vähen-tämiseen ja motoriikkaan (katapleksia ja hypo-aktiivisuus). Endokannabinoidien vaikutukset vastaavat monin osin THC:n vaikutuksia. En-dokannabinoidijärjestelmä osallistuneekin mo-toristen ja kognitiivisten toimintojen säätelyyn sekä mielihyväkokemuksen (»reward»-ilmiön) kehittymiseen. Suuria endokannabinoidipitoi-suuksia on todettu liikehäiriöissä ja hermosolu-vaurion yhteydessä. Endokannabinoidit syntetisoituvat postsynap-tisissa hermosoluissa (kuva 1), moduloivat ret-rogradisesti presynaptisten hermosolujen pinnal-la sijaitsevia reseptoreja ja vähentävät muiden hermovälittäjäaineiden vapautumista (Basavara-jappa ja Hungund 2002, Rueda ym. 2002). Muista neuromodulaattoreista poiketen endo-kannabinoideja ei vapaudu varastorakkuloista, vaan hermosolut syntetisoivat niitä nopeasti tar-peen mukaan.
... Zucker and Zucker, 1962;DiMarzo et al., 2001) and exhibits an obese phenotype. Moreover, the obese Zucker has been shown to have higher 2-AG (an endocannabinoid) levels in areas of the brain that are relevant to food intake (Wenger and Moldrich, 2002;Harrold and Williams, 2003;Jo et al., 2005), and these higher levels seem to be mediated by an insensitivity to leptin (DiMarzo et al., 2001). Few studies, have examined how these physiological changes manifest in behavioral choice that go beyond food intake as a dependent variable. ...
Article
This experiment reports on the ability of rimonabant to alter the reinforcing properties of food in the genetically obese Zucker (fa/fa) rat, a strain that exhibits higher levels of endocannabinoids in brain regions that correspond to heightened food intake. We characterized food reinforcement in obese and lean Zucker rats by placing behavior under progressive ratio schedules of sucrose reinforcement. Then, doses of rimonabant (1-10 mg/kg), a CB1 receptor antagonist, were administered. Obese Zuckers had slightly higher breakpoints for sucrose under baseline conditions compared with leans, and also demonstrated significantly higher response rates than leans. Rimonabant dose-dependently decreased breakpoints and response rates for both groups, though only obese Zuckers demonstrated suppressed behavior under the 1 mg/kg dose. The 10 mg/kg dose of rimonabant reduced breakpoints equally for both groups (by about 60%). This dose of rimonabant also reduced food intake by 20% in lean Zuckers, and by 30% in obese Zuckers. These findings extend the literature that rimonabant reduces food reinforcer efficacy, and suggest that obese Zuckers may exhibit a heightened sensitivity to rimonabant. The findings also suggest that the effort required to obtain food reinforcement may also play a role in the efficacy of rimonabant.
... While this bidirectional effect is of considerable interest as a potential therapeutic target, the mechanism by which THC causes these opposing effects is not well understood. Marijuana is also involved in regulation of feeding behaviors and body weight [22], (reviewed in [23]). These effects are blocked in a dose-dependent manner by a cannabinoid antagonist [24]. ...
Article
Adolescence is a behaviorally well-defined developmental period during which experimentation with illicit drugs such as marijuana is common. While the lasting effects of adolescent marijuana use have been studied in humans and in animal models, relatively little is known about the acute response to marijuana in adolescents. It is known that adolescent rats are more impaired by the psychoactive ingredient in marijuana, delta-9 tetrahydrocannabinol (THC), than adults in a water maze spatial learning task. However, what causes this greater sensitivity to THC-induced learning impairment is not understood. We characterized adolescent (postnatal day 30-35) and adult (postnatal day 70-75) rat cannabinoid CB1 receptor number, distribution, and functional coupling in the hippocampus, the brain which may be the site at which THC impairs spatial learning impairment. Next, we elucidated the time course of hippocampal CB1 receptor desensitization in adolescents and adults in response to daily treatment with 10 mg/kg THC. Finally, we characterized the development of tolerance to the learning impairment caused by THC in adolescent and adult rats by pre-treating them for five days with 10 mg/kg THC, and measuring learning performance in the Morris water maze. Our results indicate that agonist stimulation of the CB1 receptor in adolescent hippocampus produces less functional coupling to G proteins than adults. Also, adolescent hippocampal CB1 receptors desensitize less rapidly in response to 10 mg/kg THC treatment than those in adults. Finally, adolescent rats do not become tolerant to the learning impairment effects of 10 mg/kg THC after five days of pre-treatment, while adults do. We conclude that adolescents may be more impaired by THC than adults as a result of more slowly desensitizing hippocampal CB1 receptors, which may be due to lesser functional CB1-G protein coupling in adolescents. Dissertation
... Neuropeptide Y (NPY) and agouti-related protein-producing neurones in the ARC are activated by ghrelin to stimulate food intake, whereas serotonin from the raphe nucleus inhibits feeding (10,11). Similar to their peripheral effects, centrally-released endocannabinoids (12) increase food intake, whereas GLP-1 (8), and oxyntomodulin (13) decrease it. By contrast to ghrelin, PYY appears to have different actions according to site of administration and release. ...
Article
Two major biological players in the regulation of body weight are the gut and the brain. Peptides released from the gut convey information about energy needs to areas of the brain involved in homeostatic control of food intake. There is emerging evidence that human food intake is also under the control of cortical and subcortical areas related to reward and cognition. The extent to which gut hormones influence these brain areas is not fully understood. Novel methods combining the study of neural activity and hormonal signalling promise to advance our understanding of gut-brain interactions. Here, we review a growing number of animal and human studies using neuroimaging methods (functional magnetic resonance imaging, positron emission tomography) to measure brain activation in relation to nutrient loads and infusion of gut peptides. Implications for current and future pharmacological treatments for obesity are discussed.
... We will concentrate preferentially in reviewing the role(s) played by endocannabinoids on those adult brain functions, where DA is a key regulatory neurotransmitter, namely the control of motor function at the basal ganglia level, and the expression of some cognitive functions, including emotionality, motivation, and brain reward. Additional interactions between cannabinoids and DA have been also claimed for the hypothalamic regulation of pituitary hormone secretion [45], for the expression of key genes during brain development [16,17], for memory formation [46,47], sleep regulation [48], and retina function [49] in mammals, as well as some interactions in the brain of invertebrates [50]. However, they will not be addressed in the present review. ...
Article
Endocannabinoids and their receptors, mainly the CB(1) receptor type, function as a retrograde signaling system in many synapses within the CNS, particularly in GABAergic and glutamatergic synapses. They also play a modulatory function on dopamine (DA) transmission, although CB(1) receptors do not appear to be located in dopaminergic terminals, at least in the major brain regions receiving dopaminergic innervation, e.g., the caudate-putamen and the nucleus accumbens/prefrontal cortex. Therefore, the effects of cannabinoids on DA transmission and DA-related behaviors are generally indirect and exerted through the modulation of GABA and glutamate inputs received by dopaminergic neurons. Recent evidence suggest, however, that certain eicosanoid-derived cannabinoids may directly activate TRPV(1) receptors, which have been found in some dopaminergic pathways, thus allowing a direct regulation of DA function. Through this direct mechanism or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with DA transmission in the CNS and this has an important influence in various DA-related neurobiological processes (e.g., control of movement, motivation/reward) and, particularly, on different pathologies affecting these processes like basal ganglia disorders, schizophrenia, and drug addiction. The present review will address the current literature supporting these cannabinoid-DA interactions, with emphasis in aspects dealing with the neurochemical, physiological, and pharmacological/therapeutic bases of these interactions.
... Endocannabinoids have also been found in these tissues (Pagotto et al., 2006). It has been reported that ECs are released as retrograde messengers in the SON by magnocellular neurons (Murphy et al., 1998) and that CB1 receptors are localized within the SON (Wenger and Moldrich, 2002), suggesting that ECs could modulate OXT and VP neurons in this region. Recent reports have highlighted the interaction between the ECs and the modulation of the physiology of magnocellular neurons, since OXT and ECs cooperate to shape the electrophysiological properties of SON neurons (McDonald et al., 2008). ...
Article
Marihuana and alcohol consumption affect adversely reproduction by inhibiting the hypothalamic-pituitary-gonadal axis. The endocannabinoid system, present in the central nervous system and in peripheral tissues, participates in the regulation of hormones involved in the reproductive physiology such as luteinizing hormone, prolactin and oxytocin. This system is activated in response to pathophysiological conditions such as stress and inflammatory/infectious states as well as alcoholism and drug consumption acting as a negative modulator of reproductive function. The secretion of luteinizing hormone from the adenohypophysis is reduced, mainly through hypothalamic inhibitory action of cannabinoids and alcohol on luteinizing hormone releasing hormone release from its nervous terminals in the median eminence. This inhibitory effect is mediated, at least in part, by the activation of cannabinoid type 1 receptors. Cannabinoids also inhibit prolactin release from the lactotropes in the adenohypophysis acting locally and by increasing the release of hypothalamic dopamine mainly from tuberoinfundibular dopaminergic neurons in the external layer of the median eminence. On the contrary, ethanol stimulates prolactin release from the adenohypophysis as well as oxytocin from the neurohypophysis. Besides, endocannabinoids modulate oxytocin synthesis and release from the hypothalamic magnocellular neurons and neurohypophysis. In summary, all the results exposed in the present review suggest that there is interplay between the endocannabinoid system, hormones and neuropeptides in the control of reproduction and that this system mediates, at least in part, ethanol adverse effects on reproductive function.
... eCBs have also been found in these tissues (Pagotto et al., 2006). It has been reported that eCBs are released as retrograde messengers in the SON by magnocellular neurones (Murphy et al., 1998) and that CB 1 receptors are localized within the SON (Wenger and Moldrich, 2002), suggesting that eCBs could modulate the physiology of magnocellular neurons, in fact it was reported that there is an interaction of ECS with central hormone release in the modulation of magnocellular SON neurons synaptic physiology (Sabatier and Leng, 2006; McDonald et al., 2008). In a previous work, we demonstrated the increase of AEA synthase activity in hypothalami obtained from adult male rats peripherally injected with LPS (Fernandez-Solari et al., 2006 ). ...
Article
This study investigated the participation of the hypothalamic endocannabinoid system in the response to lipopolysaccharide (LPS) challenge evaluating oxytocin (OXT) and tumor necrosis factor-alpha (TNF-alpha) plasma levels in vivo and their release from hypothalamic fragments in vitro. LPS increased OXT and TNF-alpha release through anandamide-activation of hypothalamic cannabinoid receptor CB(1,) since the antagonist AM251 blocked this effect. Anandamide, through its receptors, also increased hypothalamic nitric oxide (NO) which inhibited OXT release, ending the stimulatory effect of the endocannabinoid. Our findings reveal a hypothalamic interaction between oxytocin, endocannabinoid and NO-ergic systems providing a regulation of the hypothalamic-neurohypophyseal axis under basal and stress conditions.
... Nach der Stillzeit sei sie aus hedonistischen Gründen rückfällig mit Cannabis geworden und habe ihren Konsum dann in den letzten 3 Jahren auf 3 -5 g Marihuana (wenn möglich "Sinsemilla" [16,17]) am Tag gesteigert. Absetzversuche würden innerhalb von 1 -2 Tagen durch quälende Entzugssymptome wie Affektlabilität, Unruhe und Schlaflosigkeit verbunden mit massivem nächtlichen Schwitzen [18] [28,29], in denen sowohl die Thermoregulation [29], TSH-Regulation [30,31] und Steuerung viszeraler Funktionen zusammenkommen würden [32]. Im Gegensatz zum Neokortex, limbischen System und Hypothalamus wurden im Hirnstamm des Menschen kaum Cannabinoid-Rezeptoren gefunden [31,33] 3 Hamilton Anxitey Score [21], unter Gabapentin. 4 Hamilton Depression Score [22], unter Gabapentin. 5 Tetrahydrocannabinol im Serum in ng/ml (GC/MS im Labor Laser zu Köln). ...
Article
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We present the course of cyclical hyperemesis most likely induced by cannabis in a young cannabis-dependent, but otherwise healthy female adult. Cyclical hyperemesis developed in parallel to increasing cannabis inhalation, and remitted completely within a few days of abstinence in a protective inpatient setting. Just as in those increasing cases which can be found in literature, the hyperemesis improved by taking a hot shower or bath at the beginning of the detoxification. This thermosensitivity, along with the detection of a central disturbance of the thyroid axis, points to the hypothalamic cannabinoid system being involved in cannabis-induced cyclical hyperemesis. The patient was followed up for 4 months without any re-occurrence of the syndrome during controlled cannabis abstinence. © Georg Thieme Verlag KG Stuttgart · New York.
... This literature stated in this term that Cannabinoid signaling system acts at least at two receptors CB1 and CB2. These receptors are situated not only in pleasure centers of the central nervous system but also in many organs linked with feeding and energy management, including the hypothalamus and the gastrointestinal tract [11]. Also, studies reported that increase in food intake and weight gain are considered to be mediated by activation of CB1 receptor [12]. ...
Article
: Ghrelin is an orexigenic peptide which is secreted from stomach. : Thirty male Wistar rats were randomly divided into five groups. Two control groups were selected, the first group received 0.5 mL water per day (vehicle group) and another group did not receive anything (control group). The other three groups were treated daily with 50, 100 or 150 mg/kg of C. sativa for 7 days, respectively. Daily energy intake of the rats was calculated for 10 days prior to the> intervention and for the 7 day intervention. To investigate changes in plasma ghrelin as a potential mechanism, an orexigenic dose (150 mg/kg) of : There was no significant difference in energy intake between control and vehicle groups. Treatment with 100 and 150 mg/kg of the extract significantly increased energy intake vs the other groups (p
... Por otro lado, el sistema endocannabinoide se ha relacionado con el control de la espermatogénesis y la fertilidad masculina ( Schuel et al., 2002). Así, la supresión de la función reproductiva por el tratamiento crónico con cannabinoides (Nahas et al., 2002) puede deberse a la acción de estos compuestos tanto a nivel hipotalámico como gonadal (Wenger et al., 2002; Maccarrone y cols., 2002; Schuel et al., 2002). ...
Article
Esta Tesis doctoral pretende, como objetivo global, evaluar el papel que desempeña el sistema cannabinoide endógeno en la adicción a drogas de abuso. Para ello nos planteamos dos objetivos básicos. El primero consiste en evaluar la posible existencia de mecanismos de dependencia a cannabinoides similares a los descritos para otras drogas de abuso. El interés que generan los cannabionoides en relación a su posible uso terapéutico en determinadas patologías ha incrementado el debate acerca de los problemas de salud resultantes de su consumo prolongado. En este sentido, es importante determinar si el consumo crónico de cannabionoides induce el desarrollo de tolerancia a cannabionoides conlleva la aparición de dependencia física con manifestaciones de abstiencia comparables a las que producen otras drogas cuando se abandona su consumo crónico, con objeto de evaluar tanto las consecuencias de la interrupción del tratamiento a largo plazo con agentes cannabinomiméticos de una patología, como los peligros de salud reales derivados del uso lúdico. Otro de los focos de estudio que ha generado una gran controversia es la posibilidad de que el consumo de cannabionoides favorezca el consumo de drogas con mayor poder adictivo. A ese respecto, existen evidencia de que el consumo de heroína, tabaco y alcohol es más habitual en individuos consumidores de cannabis. Sin embargo, las conclusiones que se obtienen en estos trabajos se basan en estudios de correlación y no en causación por lo que son necesarias ulteriores investigaciones en este ámbito. El segundo objetivo básico de esta tesis doctoral consiste en establecer desde un punto de vista bioquímico y/o farmacológico la implicación del sistema cannabinoide endógeno en la dependencia a drogas de abuso diferentes del cannabis. La localización anatómica del receptor CB1 sugiere una implicación indirecta del sistema cannabinoide endógeno en la modulación de la ruta depaminérgica mesocorticolímbica que podría ser la responsable de las acciones de los cannabinoides en los procesos de refuerzo y respuestas motivacionales pero que también pdoría afectar a la capacidad reforzante de otras drogas de abuso. Si esto es así, cabría esperar que la exposición crónica a diferentes drogas de abuso afectara a la actividad endocannabinoide sobre todo en las regiones cerebrales implicadas en la adicción. Asimismo, la manipulación farmacológica del sistema cannabinoide endógeno podría ser efectiva en los que se refiere a la atenuación del comportamiento de búsqueda compulsiva de una droga como sugieren algunos estudios
... The mechanism of CHS is still unknown. Most cannabinoids act through two receptors, CB1 and CB2, which reduce anterior pituitary hormone and increase corticotrophin release [15] . Disturbances of the hypothalamic-pituitary-adrenal axis and the presence of autonomic instability have been proposed as possible mechanisms of CHS [6] . ...
Article
Long-term cannabis use may be associated with attacks of severe nausea and vomiting, and a characteristic learned behavior of compulsive hot bathing, termed cannabinoid hyperemesis syndrome (CHS). Long-term follow-up and prognosis of CHS have not been reported previously. A 44-year-old Caucasian man with a long history of addiction to marijuana presented with chronic abdominal pain complicated by attacks of uncontrollable vomiting for 16 years. He had a compulsion to take scalding hot showers, as many as 15 times a day, to relieve his symptoms. All previous therapies had been ineffective. However, abstinence from marijuana led to rapid and complete resolution of all symptoms and his compulsive hot showering behavior. He has been followed for nine years, and is still doing well without recurrence of symptoms. Physicians should have a high index of suspicion for this under-recognized condition, as excellent long-term prognosis of CHS can be achieved when abstinence is maintained.
... Interestingly in autoradiographic assays of the CNS, to determine the location and concentration of CB 1 receptors, it was found that some places in the CNS that were associated with effects that cannabinoids produce, did not have a high concentration of receptors but had very tight G protein-coupling (Freund et al. 2003). For example, CB 1 receptors are not highly concentrated in the hypothalamus, yet the hypothalamus is affected by cannabinoids and produces the hypothermia and hunger seen when cannabinoids are consumed in humans (Wenger and Moldrich 2002). The spinal cord and brain stem are other examples of tissues with lower concentrations of CB 1 receptors yet produce significant responses when exposed to cannabinoids such as blood pressure changes and anti-emetic effects associated with the brain stem being affected, and analgesia and anti-hypernociceptive effects associated with the spinal cord (Malinowska et al. 2012;Manzanares et al. 2006). ...
Chapter
Bhanga (Cannabis) has been reported with numerous therapeutic, traditional, commercial, and sacred uses in India and across the globe. Its uses are deeply rooted in the cultural, social, and economic lives of the people. The inclusion of Cannabis under ‘Scheduled E1’ drugs in India restricts its use. However, being a crop of economic and medicinal importance, the pharmaceutical and various other sectors are showing much interest in the plant. The present review article delineates traditional, culinary, cosmetic, ritual, social, spiritual, recreational, economic, and therapeutic uses of Cannabis. The review illustrates various uses of Cannabis across the globe; noted from articles, publications, and books providing description of various parts, viz. leaves and seeds (Bhanga), flowering and fruiting tops (Ganja), resin (Charas), extract, tincture, and whole plant, stalks (Fibers). The review may be helpful to researchers, clinicians, and pharmaceutical companies to carry out further research for developing cost-effective healthcare options.
... In agreement with the tetrad results, these phase-dependent differences were not detected in the hypothalamus, a region that regulates body temperature (Figures 1B and 3A). 37,38 These data suggest that the estrus cycle's influence on CB1R activation and subsequent upregulation in total CB1R protein quantity is most detectable in the spine ( Figure 3A). Whether this receptor upregulation indicates de novo synthesis of proteins or post-translational reorganization of receptor expression on the plasma membrane remains unknown. ...
Article
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Sexual dimorphisms are observed in cannabinoid pharmacology. It is widely reported that female animals are more sensitive to the cataleptic, hypothermic, antinociceptive, and anti-locomotive effects of cannabinoid receptor agonists such as CP55,940. Despite awareness of these sex differences, there is little consideration for the pharmacodynamic differences within females. The mouse estrus cycle spans 4-5 days and consists of four sex hormone-mediated phases: proestrus, estrus, metestrus, and diestrus. The endocannabinoid system interacts with female sex hormones including β-estradiol, which may influence receptor expression throughout the estrus cycle. In the current study, sexually mature female C57BL/6 mice in either proestrus or metestrus were administered either 1 mg/kg i.p. of the cannabinoid receptor agonist CP55,940 or vehicle. Mice then underwent the tetrad battery of behavioral assays measuring catalepsy, internal body temperature, thermal nociception, and locomotion. Compared with female mice in metestrus, those in proestrus were more sensitive to the anti-nociceptive effects of CP55,940. A similar trend was observed in CP55,940-induced catalepsy; however, this difference was not significant. As for cannabinoid receptor expression in brain regions underlying antinociception, the spine tissue of proestrus mice that received CP55,940 exhibited increased expression of cannabinoid receptor type 1 relative to treatment-matched mice in metestrus. These results affirm the importance of testing cannabinoid effects in the context of the female estrus cycle.
... In the present study, the hypothermia was almost absent in control animals injected with CP55,940. The ability of cannabinoids to interfere with thermoregulation is attributed to their interaction with CB receptors in the hypothalamus ( (Wenger and Moldrich, 2002). Intrathecal administration of cannabinoids may limit the interaction with non-spinal sites and led to less pronounced effect on thermoregulation. ...
Article
Cannabinoid (CB) receptor agonists show robust antinociceptive effects in various pain models. However, most of the clinically potent CB1 receptor-active drugs derived from cannabis are considered concerning due to psychotomimetic side effects. Selective CB receptor ligands that do not induce CNS side effects are of clinical interest. The venoms of marine snail Conus are a natural source of various potent analgesic peptides, some of which are already FDA approved. In this study we evaluated the ability of several Conus venom extracts to interact with CB1 receptor. HEK293 cells expressing CB1 receptors were treated with venom extracts and CB1 receptor internalization was analyzed by immunofluorescence. Results showed C. textile (C. Tex) and C. miles (C. Mil) samples as the most potent. These were serially subfractionated by HPLC for subsequent analysis by internalization assays and for analgesic potency evaluated in the formalin test and after peripheral nerve injury. Intrathecal injection of C. Tex and C. Mil subfractions reduced flinching/licking behavior during the second phase of formalin test and attenuated thermal and mechanical allodynia in nerve injury model. Treatment with proteolytic enzymes reduced CB1 internalization of subfractions, indicating the peptidergic nature of CB1 active component. Further HPLC purification revealed two potent antinociceptive subfractions within C. Tex with CB1 and possible CB2 activity, with mild to no side effects in the CB tetrad assessment. CB conopeptides can be isolated from these active Conus venom-derived samples and further developed as novel analgesic agents for the treatment of chronic pain using cell based or gene therapy approaches.
... Furthermore, it is also engaged in body temperature homeostasis (Wenger and Moldrich, 2002). Besides, CBRs are expressed in the spinal cord (where they play a role in the modulation of pain signalling) (Starowicz and Finn, 2017), peripherally in sensory neurons and the autonomic nervous system e what depends on modulation of numerous peripheral effects, such as vasodilatation and tachycardia (Pacher et al., 2005). ...
Chapter
Biologically active substances are an inherent element of human and plant coexistence. Preparations made of Cannabis have been recognized for centuries by science, among others for their therapeutic properties. However, they have also become a narcotic prohibited by law. Legal restrictions on the marketing of Cannabis plant raw material are the main factors inhibiting efforts of expanding knowledge about the rich spectrum of substances formed by the plant. In the last decades, the boundary of discrepancy between perceptions of science and law has become blurred due to numerous evidence showing the benefits of constituents occurring in the plant for applications in medicine. Cannabis sp. and its products consist of a large variety of chemicals. A significant part of identified cannabinoids, terpenes, terpenoids or flavonoids, the most abundant classes, are proven to have medicinal properties. The above-mentioned secondary metabolites of Cannabis sp. appear to be promising pharmaceuticals. They have an impact on many physiological processes occurring in humans, mainly due to acting on the endocannabinoid system, having farfetched importance to human physiology, starting from embryo implantation and fetal development through the functioning of the immune system, regulating cognitive and motor processes, modulating the course of the inflammatory reaction and ending on autophagy and apoptosis.
... Treatment with the anorexigenic leptin peptide decreases EDMP levels in normal rats and obese (ob/ob) mice, indicating that molecules with a distinct chemical nature (i.e., peptides and plasma membrane phospholipid-derived compounds) can control food intake and energy balance [120]. Together, these findings provide evidence of the role of hypothalamic peptides and EDMP in food intake and appetite regulation [121]. ...
Article
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Overweight and obesity are among the most prominent health problems in the modern world, mostly because they are either associated with or increase the risk of other diseases such as type 2 diabetes, hypertension, and/or cancer. Most professional organizations define overweight and obesity according to individual body-mass index (BMI, weight in kilograms divided by height squared in meters). Overweight is defined as individuals with BMI from 25 to 29, and obesity as individuals with BMI ≥30. Obesity is the result of genetic, behavioral, environmental, physiological, social, and cultural factors that result in energy imbalance and promote excessive fat deposition. Despite all the knowledge concerning the pathophysiology of obesity, which is considered a disease, none of the existing treatments alone or in combination can normalize blood glucose concentration and prevent debilitating complications from obesity. This review discusses some new perspectives for overweight and obesity treatments, including the use of the new orally active cannabinoid peptide Pep19, the advantage of which is the absence of undesired central nervous system effects usually experienced with other cannabinoids.
... The endocannabinoid system in the hypothalamus is a critical brain region involved in thermoregulation. 162,163 Low doses of THC cause hyperthermia, whereas high doses produce hypothermia 26,164 by activating CB 1 receptors in the hypothalamus. 165 As previously mentioned, hot baths and showers consistently decrease nausea and vomiting symptoms for individuals experiencing CHS. ...
Article
Introduction: Cannabinoids have long been known for their ability to treat nausea and vomiting. Recent reports, however, have highlighted the paradoxical proemetic effects of cannabinoids. Cannabinoid hyperemesis syndrome (CHS) is characterized by cyclical episodes of nausea and vomiting, accompanied by abdominal pain following prolonged, high-dose cannabis use, which is alleviated by hot baths and showers. Little is known about the cause of this syndrome. Discussion: Cannabinoids produce a biphasic effect on nausea and vomiting, with low doses having an antiemetic effect and high doses producing emesis. Presentation and treatment of CHS are similar to cyclical vomiting syndrome as well as chemotherapy-related anticipatory nausea and vomiting, suggesting that these phenomena may share mechanisms. The prevalence of CHS is not known because of the symptomatic overlap with other disorders and the lack of knowledge of the syndrome by the public and physicians. Treatment with typical antiemetic drugs is ineffective for CHS, but anxiolytic and sedative drugs, along with hot showers, seem to be consistently effective at reducing symptoms. The only known way to permanently end CHS, however, is abstinence from cannabinoids. Case studies and limited pre-clinical data on CHS indicate that prolonged high doses of the main psychotropic compound in cannabis, Δ9-tetrahydrocannabinol (THC), result in changes to the endocannabinoid system by acting on the cannabinoid 1 (CB1) receptor. These endocannabinoid system changes can dysregulate stress and anxiety responses, thermoregulation, the transient receptor potential vanilloid system, and several neurotransmitters systems, and are thus potential candidates for mediating the pathophysiology of CHS. Conclusions: Excessive cannabinoid administration disrupts the normal functioning of the endocannabinoid system, which may cause CHS. More clinical and pre-clinical research is needed to fully understand the underlying pathophysiology of this disorder and the negative consequences of prolonged high-dose cannabis use.
... 15 For example, anandamide produces analgesia, 16 hypothermia, hypomotility, and catalepsy. 17,18 Likewise, anandamide induces overeating in rats treated with rather low doses (0.5-10 mg/kg) 19 . Finally, it has been shown that anandamide ...
Chapter
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The endogenous cannabinoids are molecules synthesized by animals, from insects to mammals, that generate effects similar to those produced by marijuana (Figure 25.1). 1 The generic name of these molecules, known as endocannabinoids, derives from the scientific name of marijuana (Cannabis sativa) and its more abundant natural components, the cannabinoids. There are several endogenous cannabinoids produced by the brain, and other molecules that have cannabinoid-like activity, although they do not bind to the cannabinoid receptor (Table 25.1). Oleamide is an example of a molecule that binds to the CB1 and CB2 receptors only at high concentrations, 2 and thus is considered to be an atypical or weak endocannabinoid. All these molecules are lipids and differ from the classic neurotransmitters in several ways. For example, classic neurotransmitters such as catecholamines or acetylcholine are synthesized and stored in synaptic vesicles from which they are released as a result of neuron depolarization. Endocannabinoids, instead, are synthesized from membrane lipid precursors and released immediately thereafter, as a response to activation of membrane receptors. They are not, therefore, stored at any point during or after synthesis. In addition, their transmission is retrograde 3 (Figure 25.2). All in all, the most fascinating aspect of these molecules is the potential physiological processes they might regulate in normal subjects, one of which is the sleep-waking cycle.
... Data have been reported concerning the effects of cannabinoids on prolactin levels; in particular, the administration of THC into the third cerebral ventricle of rats reduced plasma prolactin amounts [242]. Indeed, AEA and cannabinoids inhibited prolactin's production from the pitui- tary [242][243][244]. Given the relevance of the complex prolac- tin/prolactin receptor in neuro-inflammation related to MS, further investigation of the relationship among prolactin, cannabinoids, and the immune system might provide novel approaches into the therapeutic potential of the complex prolactin /prolactin receptor in the therapy of MS. ...
Article
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Background: Cannabinoid receptors are involved in the neuro-pathogenic mechanisms of inflammatory conditions of the central nervous system and their expression can be modulated during diseases. Methods: In this manuscript we highlight the function of cannabinoid receptors, their signalling and expression at peripheral and central levels in order to understand their implication in neuro-inflammation and review the effects of cannabinoids in neuro-inflammatory disorders. Results: Brain inflammatory processes are characterized by infiltration of numerous types of cells: both peripheral and brain resident immune cells and other neuronal cells. The disruption of the blood brain barrier favours cell infiltration in the central nervous system with consequent neuronal damage, a common event in many neuro-inflammatory diseases. Cannabinoids affect brain adaptive and immune response, regulate inflammatory mediators and can exert a role in blood brain barrier damage prevention. Conclusion: Various patents describe the beneficial properties of cannabinoids in numerous neurodegenerative diseases with inflammatory components and overall effects support the therapeutic application of cannabinoids.
... It has also been described that cannabinol and THC inhibit specific binding of dihydrotestosterone to the androgen receptor in the prostate gland (Purohit et al., 1980). Moreover, there is evidence that suggests that the endocannabinoid system has an important role in the regulation of endocrine functions, and recent results support the consideration of endocannabinoids as neuroendocrine modulators (Wenger et al., 2001;Maccarrone et al., 2002Maccarrone et al., , 2003Wenger & Moldrich, 2002). Accordingly, it is of importance to determine the mechanisms of degradation of endocannabinoids, in particular anandamide as the most representative one, in target glands of the hypothalamicpituitary-gonadal axis. ...
Article
The response of anandamide is terminated by a carrier-mediated transport followed by degradation catalyzed by the cloned enzyme fatty acid amidohydrolase (FAAH). In this study, we provide biochemical data showing an anandamide uptake process and the expression of FAAH in human prostate. Anandamide was accumulated in PC-3 cells by a saturable and temperature-dependent process. Kinetic studies of anandamide uptake, determined in the presence of cannabinoid and vanilloid antagonists, revealed apparent parameters of KM=4.7±0.2 μM and Vmax=3.3±0.3 pmol min−1 (106 cells)−1. The accumulation of anandamide was moderately inhibited by previously characterized anandamide transporter inhibitors (AM404, UCM707 and VDM11) but was unaffected by inhibitors of other lipid transport systems (phloretin or verapamil) and moderately affected by the FAAH inhibitor methyl arachidonyl fluorophosphonate. The presence of FAAH in human prostate epithelial PC-3 cells was confirmed by analyzing its expression by Western blot and measuring FAAH activity. To further study the structural requirements of the putative carrier, we synthesized a series of structurally different compounds 1–8 and evaluated their capacity as uptake inhibitors. They showed different inhibitory capacity in PC-3 cells, with (9Z,12Z)-N-(fur-3-ylmethyl)octadeca-9,12-dienamide (4, UCM119) being the most efficacious, with maximal inhibition and IC50 values of 49% and 11.3±0.5 μM, respectively. In conclusion, PC-3 cells possess a complete inactivation system for anandamide formed by an uptake process and the enzyme FAAH. These results suggest a possible physiological function of anandamide in the prostate, reinforcing the role of endocannabinoid system as a neuroendocrine modulator. British Journal of Pharmacology (2004) 141, 457–467. doi:10.1038/sj.bjp.0705628
Article
Appetite is governed by peripheral hormones and central neurotransmitters that act on the arcuate nucleus of the hypothalamus and nucleus tactus solitarius of the brainstem. Cancer anorexia appears to be the result of an imbalance between neuropeptide-Y and pro-opiomelanocortin signals favoring pro-opiomelanocortin. Many of the appetite stimulants redress this imbalance. Most of our understanding of appetite neurophysiology and tumor-associated anorexia is derived from animals and has not been verified in humans. There have been few clinical trials and very little translational research on anorexia despite its prevalence in cancer.
Article
Dietary long-chain polyunsaturated fatty acids are known to influence brain levels of the endocannabinoid anandamide in newborn pigs and mice. Furthermore, endocannabinoids were shown to control pup suckling and body weight in mice, and food intake in adult rodents. Here we determined the effect of maternal under-nutrition during gestation, lactation, or both, on body weight, and on the levels of endocannabinoids and expression of cannabinoid CB1 receptors and fatty acid amide hydrolase in the hypothalamus of rat pups at weaning (21 days old) or adult rats (4 months old). Maternal under-nutrition resulted in a striking decrease in body weight of weaning rats, paralleled by a decrease in the hypothalamic levels of the endocannabinoid anandamide, but not of 2-arachidonoylglycerol. No significant change in the hypothalamic expression of either cannabinoid CB1 receptors or fatty acid amide hydrolase mRNA was detected in any of the three groups of weaned pups. The decrease in pup body weight and hypothalamic anandamide levels was not observable in 4-month-old rats from any of the three groups. These data suggest that maternal under-nutrition causes a decrease in hypothalamic anandamide levels and loss of body weight, and confirm a crucial role for endocannabinoid signalling in neonatal development.
Article
The endocannabinoid arachidonylethanolamide (AEA, anandamide) is an endogenous ligand for the cannabinoid receptors and has been shown to be oxygenated by cyclooxygenase-2 (COX-2). We examined the structural requirements for COX-mediated, AEA oxygenation using a number of substrate analogues and site-directed mutants of COX-2. Fourteen AEA analogues were synthesized and tested as COX substrates. These studies identified the hydroxyl moiety of AEA as a critical determinant in the ability of COX enzymes to effect robust endocannabinoid oxygenation. In addition, these studies suggest that subtle structural modifications of AEA analogues near the ethanolamide moiety can result in pronounced changes in their ability to serve as COX-2 substrates. Site-directed mutagenesis studies have permitted the development of a model of AEA binding within the COX-2 active site. As with arachidonic acid, the omega-terminus of AEA binds in a hydrophobic alcove near the top of the COX-2 active site. The polar ethanolamide moiety of AEA, like the carboxylate of arachidonate, interacts with Arg-120 at the bottom of the COX-2 active site. Mutation of Tyr-385 prevents AEA oxygenation, suggesting that, as in the case of other COX substrates, AEA metabolism is initiated by Tyr-385-mediated hydrogen abstraction. Thus, AEA binds within the COX-2 active site in a conformation roughly similar to that of arachidonic acid. However, important differences have been identified that account for the isoform selectivity of AEA oxygenation. Importantly, the COX-2 side pocket and Arg-513 in particular are critical determinants of the ability of COX-2 to efficiently generate prostaglandin H(2) ethanolamide. The reduced efficiency of COX-1-mediated, AEA oxygenation can thus be explained by the absence of an arginine residue at position 513 in this isoform. Mutational analysis of Leu-531, an amino acid located directly across from the COX-2 side pocket, suggests that AEA is shifted away from this hydrophobic residue and toward Arg-513 relative to arachidonic acid. Coupled with earlier observations with the endocannabinoid 2-arachidonylglycerol, these results indicate that one possible function of the highly conserved COX-2 active site side pocket is to promote endocannabinoid oxygenation.
Article
The last decade has witnessed a rapid expansion in our understanding of the mammalian endogenous cannabinoid system. In just a few short years since the discovery of endogenous lipids that serve as cannabinoids in vivo, these molecules have been shown to participate in a broad array of physiological and pathological processes. Consequently, attention has been directed at defining the proteins responsible for endocannabinoid synthesis, transport, and metabolism. Recently, multiple fatty acid oxygenases including, most notably, cyclooxygenase-2 (COX-2), have been implicated in endocannabinoid metabolism. This review will highlight connections between COX-2 and the endogenous cannabinoid system. The available biochemical evidence supporting a role for COX-2 in endocannabinoid metabolism will be presented. Finally, the potential biological consequences of COX-2-mediated endocannabinoid oxygenation will be discussed.
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The phenomenon of functional selectivity, whereby a ligand preferentially directs the information output of a G-protein coupled receptor (GPCR) along (a) particular effector pathway(s) and away from others, has redefined traditional GPCR signaling paradigms to provide a new approach to structure-based drug design. The two principal cannabinoid receptors (CBRs) 1 and 2 belong to the class-A GPCR subfamily and are considered tenable therapeutic targets for several indications. Yet conventional orthosteric ligands (agonists, antagonists/inverse agonists) for these receptors have had very limited clinical utility due to their propensity to incite on-target adverse events. Chemically distinct classes of cannabinergic ligands exhibit signaling bias at CBRs toward individual subsets of signal transduction pathways. In this review, we discuss the known signaling pathways regulated by CBRs and examine the current evidence for functional selectivity at CBRs in response to endogenous and exogenous cannabinergic ligands as biased agonists. We further discuss the receptor and ligand structural features allowing for selective activation of CBR-dependent functional responses. The design and development of biased ligands may offer a pathway to therapeutic success for novel CBR-targeted drugs.
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The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
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Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
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Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
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The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
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Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors. Furthermore it shows no affinity for any of the more than 70 receptors, ion channels or enzymes investigated (IC50 > 10 microM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 microM). Furthermore, SR 144528 is able to selectively block the mitogen-activated protein kinase activity induced by CP 55,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 microM is found. In addition, SR 144528 is shown to antagonize the stimulating effects of CP 55,940 on human tonsillar B-cell activation evoked by cross-linking of surface Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 totally displaced the ex vivo [3H]-CP 55,940 binding to mouse spleen membranes (ED50 = 0.35 mg/kg) with a long duration of action. In contrast, after the oral route it does not interact with the cannabinoid receptor expressed in the mouse brain (CB1). It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.
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Anandamide is the newly discovered endogenous cannabinoid ligand that binds to brain cannabinoid receptors and shares most, but not all, of the pharmacological properties of delta 9-THC. Therefore, this study was undertaken to determine whether its interaction with the CB1 receptor in brain was identical to that of delta 9-THC. Anandamide depressed spontaneous activity and produced hypothermia, antinociception and immobility in mice after i.v. administration. However, none of these effects was blocked by pretreatment with the selective CB1 antagonist, SR 141716A. However, the metabolically stable analog 2-methyl-2'-fluoroethylanandamide produced reductions in motor activity and antinociception in mice, effects that were blocked by the antagonist. To determine whether anandamide's receptor binding mimicked that of other cannabinoids, an autoradiographic comparison of anandamide, SR 141716A and CP 55,940 competition for [3H]CP55,940 binding was conducted throughout rat brain. The receptor affinities for all three compounds did not change according to brain area. As expected, Bmax values differed dramatically among differ brain areas. However, the Bmax values for each brain area were similar regardless of the compound used for displacement. These data suggest that anandamide, SR 141716A and CP 55,940 compete for the same cannabinoid receptor throughout brain despite SR 141716A's failure to block anandamide's pharmacological effects. Although there is no question that anandamide binds to the cannabinoid receptor, failure of SR 141716A to block its pharmacological effects in mice poses a dilemma. The results presented herein raise the possibility that anandamide may not be producing all of its effects by a direct interaction with the CB1 receptor.
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Using a pre-feed paradigm, the effects of orally-administered delta9-tetrahydrocannabinol (THC) on low baseline levels of nocturnal feeding were assessed. Following 2-h access to a palatable wet mash diet at dark onset, adult male Lister hooded rats (Charles River) were treated with either sesame seed oil vehicle or delta9- tetrahydrocannabinol (0.063, 0.12, 0.25, 0.5, 1.0, or 2.0 mg/kg). One hour later, rats were allowed ad libitum access to standard chow, and intakes were monitored over the subsequent 24 h. Doses of 0.5, 1.0, and 2.0 mg/kg produced substantial hyperphagia during the first hour of testing. Subsequently, rats compensated for their overconsumption so that 24-h intakes were similar in all conditions. The data confirm anecdotal reports of the orexigenic actions of exogenous cannabinoids and suggest a critical role for endogenous cannabinoid systems in the regulation of appetite.
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Two subtypes of cannabinoid receptors have been identified to date, the CB, receptor, essentially located in the CNS, but also in peripheral tissues, and the CB2 receptor, found only at the periphery. The identification of Δ9-tetrahydrocannabinol (Δ9-THC) as the major active component of marijuana (Cannabis sativa), the recent emergence of potent synthetic ligands and the identification of anandamide and sn-2 arachidonylglycerol as putative endogenous ligands for cannabinoid receptors in the brain, have contributed to advancing cannabinoid pharmacology and approaching the neurobiological mechanisms involved in physiological and behavioral effects of cannabinoids. Most of the agonists exhibit nonselective affinity for CB1/CB2 receptors, and Δ9-THC and anandamide probably act as partial agonists. Some recently synthesized molecules are highly selective for CB2 receptors, whereas selective agonists for the CB1 receptors are not yet available. A small number of antagonists exist that display a high selectivity for either CB1 or CB2 receptors. Cannabinomimetics produce complex pharmacological and behavioral effects that probably involve numerous neuronal substrates. Interactions with dopamine, acetylcholine, opiate, and GABAergic systems have been demonstrated in several brain structures. In animals, cannabinoid agonists such as Δ9-THC, WIN 55,212-2, and CP 55,940 produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity, and catalepsy. They are reversed by the selective CB1 receptor antagonist, SR 141716, providing good evidence for the involvement of CB1-related mechanisms. Anandamide exhibits several differences, compared with other agonists. In particular, hypothermia, analgesia, and catalepsy induced by this endogenous ligand are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, inflammatory, and immune responses. Agonists may induce biphasic effects, for example, hyperactivity at low doses and severe motor deficits at larger doses. Intriguingly, although cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of Δ9-THC, WIN 55,212-2, and CP 55,940 is more readily obtained in a variety of tests. The selective blockade of CB1 receptors by SR 141716 impaired the perception of the appetitive value of positive reinforcers (food, cocaine, morphine) and reduced the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, by using SR 141716 as a tool, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, faced with anxiogenic stimuli or highly motivational reinforcers. Some effects of SR 141716 also suggest that CB1-related mechanisms exert a tonic control on cognitive processes. Extensive basic research is still needed to elucidate the roles of cannabinoid systems, both in the brain and at the periphery, in normal physiology and in diseases. Additional compounds, such as selective CB1 receptor agonists, ligands that do not cross the blood brain barrier, drugs interfering with synthesis, degradation or uptake of endogenous ligand(s) of CB receptors, are especially needed to understand when and how cannabinoid systems are activated. In turn, new therapeutic strategies would likely to emerge.
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The “constancy of the internal milieu,” as described by Claude Bernard in 1859, is essential for the survival of any warm-blooded animal, and its maintenance requires strict control over behavioral, autonomic, and endocrine responses to the environment. The hypothalamus has clearly evolved as the major integrative center for regulating all of these homeostatic control systems. The location of the hypothalamus—superior to the hypophysis, and adjacent to subcortical “limbic” structures—suggests this role, as it is uniquely positioned to both send and receive endocrine signals, as well as neural signals from sensory organs, memory centers, and autonomic circuitries. Incoming information is registered, analyzed, and integrated in hypothalamic neurons. On the basis of these calculations, the hypothalamus effects the changes, if needed, in hormone secretions, behavioral state, and autonomic activity. The hypothalamus is thus responsible for monitoring the internal and external environment and coordinating adaptive physiological responses among several systems.
Article
Most data on effects of natural and synthetic cannabinoids on anterior pituitary hormone secretion point out to a primary impact on the hypothalamus. There is also some evidence, however, of possible direct actions of these compounds on the anterior pituitary, although the presence of cannabinoid receptors in the pituitary has not been documented as yet. In the present study, we evaluated the presence of cannabinoid CB1 receptor-mRNA transcripts in the pituitary gland by in situ hybridization. We observed CB1 receptor-mRNA transcripts in the anterior pituitary and to a lesser extent in the intermediate lobe whereas they were absent in the neural lobe. We then examined whether CB1 receptor-mRNA levels in both pituitary lobes responded to chronic activation by a specific agonist, as did receptors located in adjacent hypothalamic nuclei and in other brain regions. Daily administration of CP-55,940 for 18 days produced a small, but statistically significant paradoxical increase in CB1 receptor-mRNA levels in the anterior pituitary, with no changes in the intermediate lobe, in contrast to reduced CB1 receptor-mRNA levels observed in the ventromedial hypothalamic nucleus (VMN), and to decreased CB1 receptor binding in the VMN and the arcuate nucleus. The time-course of up-regulation of CB1 receptor-mRNA transcripts in the anterior lobe was biphasic; daily administration of Δ9-tetrahydrocannabinol produced an early and marked decrease in CB1 receptor-mRNA levels after 1 and 3 days, followed by normalization after 7 days and by a small increase after 14 days. We also checked whether endogenous cannabinoid ligands are present in the anterior pituitary and the hypothalamus. Although anandamide itself was detected only in trace amounts, concentrations of its precursor N-arachidonoyl-phosphatidyl-ethanolamine and of 2-arachidonoyl-glycerol were found in both tissues, suggesting that endocannabinoids may be synthetized in the anterior pituitary. In summary, CB1 receptors and corresponding ligands seem to be expressed in cells of the anterior and intermediate lobes of the pituitary, but the response of CB1 receptor-mRNA transcripts in the anterior lobe to chronic agonist activation is different than the desensitization observed in hypothalamic nuclei.
Article
The present study was aimed to test whether the endogenous ligand for the cannabinoid receptor, anandamide (ANA) could produce direct effects on anterior pituitary (AP) hormone secretion in vitro. AP cells, dispersed in Krebs-Ringer, were treated with either (1) different concentrations of ANA, (2) with ANA after pre-treatment with the selective central cannabinoid receptor (CB1) antagonist, SR 141716 (SR) or (3) with SR alone. After 30 min of incubation the luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), adrenocorticotroph hormone (ACTH) as well as growth hormone (GN), were measured in the culture media. All these hormone levels were affected with the exception of FSH, which did not change after the treatment. LH and PRL levels were decreased while ACTH and GH increased. The LH and PRL decrease were prevented by SR. SR did not antagonize the stimulatory effect exerted by ANA on ACTH and GH release from AP cells. We postulate that ANA inhibits or activates the release and/or synthesis of AP hormones. This activation may occur via CBI receptor in the case of LH and PRL; the other effects of the endogenous cannabinoids are probably mediated via another postulated (CBx) receptor for which SR is not an effective antagonist. The results indicate that ANA may influence AP hormone secretion, acting directly on the gland.
Article
Six male Lewis rats were tested for the effect of Δ9-tetrahydrocannabinol (Δ9-THC) on feeding evoked by electrical stimulation of the lateral hypothalamus. Treatment with Δ9-THC (0.4 mg/kg IP) decreased frequency threshold for feeding by 20.5% (±4.3), causing a leftward shift in the function relating stimulation frequency to the latency to begin eating 45-mg food pellets upon stimulation onset; there was no change in the asymptotic performance that was approached with sufficiently high stimulation frequencies. Naloxone (1 and 2 mg/kg) reduced the facilitory effect of Δ9-THC, but did so at doses that can inhibit feeding in the no-drug condition. These data are consistent with evidence implicating endogenous opioids in feeding, and suggest (but do not confirm) that the facilitation of feeding by Δ9-THC may be mediated by endogenous opioids. The facilitation of stimulation-induced feeding by doses of Δ9-THC that have been found to facilitate brain stimulation reward is consistent with evidence suggesting common elements in the brain mechanisms of these two behavioral effects of medial forebrain bundle stimulation.
Article
Arab scientists were several centuries ahead of our current knowledge of the curative power of hemp (Cannabis sativaL., Cannabaceae). Modern Western scientific literature ignores their contribution on the subject. We review in this paper the therapeutic uses of the plant in Arabic medicine from the 8th to the 18th century. Arab physicians knew and used its diuretic, anti-emetic, anti-epileptic, anti-inflammatory, painkilling and antipyretic properties, among others.
Article
Anandamine (arachidonylethanolamide), an arachidonic acid derivative isolated from the porcine brain, displays binding characteristics indicative of an endogenous ligand for the cannabinoid receptor. The functional activity of anandamide was tested in vivo using behavioral and physiological paradigms in laboratory rodents. At IP doses from 2 to 20 mg/kg in mice, anandamide significantly decreased spontaneous motor activity in a Digiscan open field. Rectal body temperature significantly decreased at doses of 10 and 20 mg/kg in rats. At doses from 0.03 to 30 mg/kg, anandamide had no significant effect on chow consumption in ad lib fed rats. Over the dose range of 2–20 mg/kg, anandamide did not show anxiolytic properties in the mouse light ⇌ dark exploration model of anxiety. Over the dose range of 0.3–3 mg/kg, anandamide had no effect on choice accuracy or session duration in the delayed nonmatching to sample memory task (DNMTS) in rats. These results demonstrate that anandamide has biological and behavioral effects in awake rodents, some of which are similar to the reported actions of THC.
Article
The presence of central cannabinoid receptor (CB1), involving the N-terminal 14 amino acid peptide, was demonstrated in the rat brain by immunohistochemistry. Intensely stained neurons were observed in the principal neurons of the hippocampus, striatum, substantia nigra, cerebellar cortex, including the Purkinje cells. Moderate CB1-IR cell bodies and fibers were present in the olfactory bulb, cingulate, entorhinal and piriform cortical areas, amygdala and nucleus accumbens. The perivascular glial fibers have shown moderate to high density CB1-IR in olfactoric and limbic structures. Low density was detected in the thalamus and hypothalamus and area postrema. The CB1 receptor was widely distributed in the forebrain and sparsely in the hindbrain.These new data support the view that the endogenous cannabinoids play an important role in different neuronal functions as neuromodulators or neurotransmitters.
Article
It has been shown that the main psychoactive component of marihuana, Δ9tetrahydrocannabinol (THC) has mainly inhibitory effects on the regulation of reproduction. Recently, the purification and availability of the endogenous ligand of the cannabinoid receptor, arachidonyl ethanolamide, anandamide, (ANA) and its specific long lasting antagonist, the SR 141716 (SR) provided us the opportunity to compare the effects of THC and ANA on the neuroendocrine regulation of reproduction. ANA decreases serum luteinizing hormone (LH) and prolactin (PRL) levels in rats of both sexes. It has no action on serum follicle stimulating hormone (FSH) level. When ANA was administered to pregnant rats it resulted in an increase of the duration of pregnancy and in the frequency of stillbirths. The postnatal development of hypothalamo-pituitary axis in offspring was temporarily inhibited. In conclusion, we found that exogenous and endogenous cannabinoids have only slightly different effects on the reproductive parameters. These effects may occur via the central cannabinoid receptor. It is possible that the sites of action are at both hypothalamic and pituitary levels. The results further support the view that ANA may be a central neurotransmitter or neuromodulator.
Article
We studied the cannabimimetic properties of N-vanillyl-arachidonoyl-amide (arvanil), a potential agonist of cannabinoid CB1 and capsaicin VR1 receptors, and an inhibitor of the facilitated transport of the endocannabinoid anandamide. Arvanil and anandamide exhibited similar affinities for the cannabinoid CB1 receptor, but arvanil was less efficacious in inducing cannabinoid CB1 receptor-mediated GTPγS binding. The Ki of arvanil for the vanilloid VR1 receptor was 0.28 μM. Administered i.v. to mice, arvanil was 100 times more potent than anandamide in producing hypothermia, analgesia, catalepsy and inhibiting spontaneous activity. These effects were not attenuated by the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide·HCl (SR141716A). Arvanil (i.t. administration) induced analgesia in the tail-flick test that was not blocked by either SR141716A or the vanilloid VR1 antagonist capsazepine. Conversely, capsaicin was less potent as an analgesic (ED50 180 ng/mouse, i.t.) and its effects attenuated by capsazepine. The analgesic effect of anandamide (i.t.) was also unaffected by SR141716A but was 750-fold less potent (ED50 20.5 μg/mouse) than capsaicin. These data indicate that the neurobehavioral effects exerted by arvanil are not due to activation of cannabinoid CB1 or vanilloid VR1 receptors.
Article
The long history of the medicinal use of Cannabis sativa and, more recently, of its chemical constituents, the cannabinoids, suggests that also the endogenous ligands of cannabinoid receptors, the endocannabinoids, and, particularly, their derivatives may be used as therapeutic agents. Studies aimed at correlating the tissue and body fluid levels of endogenous cannabinoid-like molecules with pathological conditions have been started and may lead to identify those diseases that can be alleviated by drugs that either mimic or antagonize the action of these substances, or modulate their biosynthesis and degradation. Hints for the therapeutic applications of endocannabinoids, however, can be obtained also from our previous knowledge of marijuana medicinal properties. In this article, we discuss the anti-tumor and anti-inflammatory activity of: (1) the endocannabinoids anandamide (arachidonoylethanolamide) and 2-arachidonoyl glycerol; (2) the bioactive fatty acid amides palmitoylethanolamide and oleamide; and (3) some synthetic derivatives of these compounds, such as the N-acyl-vanillyl-amines. Furthermore, the possible role of cannabimimetic fatty acid derivatives in the pathological consequences of cancer and inflammation, such as cachexia, wasting syndrome, chronic pain and local vasodilation, will be examined.
Article
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
Article
The effect of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight was assessed in adult, non-obese Wistar rats. The daily administration of SR 141716 (2.5 and 10 mg/kg; i.p.) reduced dose-dependently both food intake and body weight. Tolerance to the anorectic effect developed within 5 days; in contrast, body weight in SR 141716-treated rats remained markedly below that of vehicle-treated rats throughout the entire treatment period (14 days). The results suggest that brain cannabinoid receptors are involved in the regulation of appetite and body weight.
Article
The function of central cannabinoid (CB1) receptor was investigated in the regulation of the pituitary–gonad axis in CB1 receptor knockout male mouse. Serum luteinizing hormone (LH) and testosterone (T) levels and basal T secretion in vitro of testes were significantly decreased in mutant (CB1−/−) mice. The receptor agonist, anandamide (ANA), suppressed LH and T secretion in wild type (CB1+/+) mice but had no effect in receptor inactivated animals. The results are the first descriptions indicating the direct action of CB1 receptors on LH and T secretion and the immunohistological demonstration of CB1 receptors in the Leydig cells. The results also indicate that CB1 receptors are responsible for the effects of exogenous cannabinoids on reproductive functions.
Article
This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.
Article
Prepared for: School of Medicine. Thesis (Ph. D.)--Virginia Commonwealth University, 1996. Includes bibliographical references (leaves 86-100).
Article
Administration of delta-9-tetrahydrocannabinol (delta 9-THC) to pro-oestrous rats (5 mg/kg and 10 mg/kg, i.p. for 10 days) decreased the hypothalamic LH-RH content. Serum prolactin levels were reduced but serum LH and FSH and pituitary hormone content were similar to values in dioestrous rats. It is suggested that delta 9-THC acts primarily on the hypothalamus.
Article
Body weight and caloric intake were measured in a group of heavy and casual marihuana users prior to, during and following 21 days of marihuana smoking under research ward conditions. A group of control subjects were studied under identical conditions, but they did not smoke marihuana. Both heavy and casual marihuana users had a significant increase in caloric intake and gained weight during the marihuana smoking period. Heavy and casual users gained an average of 3.7 and 2.8 lbs respectively during the first 5 days of marihuana smoking. In contrast, control subjects gained only a small amount of weight (0.2 lbs) during the same time interval. Water retention did not appear to be a major factor in weight gain by the marihuana users. These findings are in agreement with both anecdotal reports and previous experimental data that marihuana use is associated with increased caloric intake and weight gain.
Article
The neuronal distribution of cannabinoid receptor in the adult rat brain is reported, combining receptor binding radioautography using the synthetic psychoactive cannabinoid ligand CP55,940 with in situ hybridization histochemistry using oligonucleotide probes complementary to rat cannabinoid receptor cDNA. In the cerebral cortex, especially in the frontal and cingulate cortex, dense binding was found in layers I and VI together with slight mRNA levels in a majority of both pyramidal and non-pyramidal-shaped neurons and of high mRNA levels in a moderate number of non-pyramidal-shaped neurons especially in layers II-III and V-VI. In the hippocampal dentate gyrus, very dense staining was found in the molecular layer together with high mRNA levels in a moderate number of hilar neurons close to the granular layer. In Ammon's horn, especially in the CA3 sector, very dense binding was found in the dendritic layers together with slight mRNA levels in the majority of the pyramidal cells and high mRNA levels in a moderate number of interneurons. In the basal ganglia, binding was very dense in the lateral putamen, substantia nigra pars reticulata, globus pallidus and entopeduncular nucleus, moderate in the medial putamen and caudate; and slight in the accumbens, together with slight to moderate mRNA levels in the striatal medium-sized neurons. Together with slight binding, slight to moderate mRNA levels were found in the majority of the neurons in the subthalamic nucleus. No binding and mRNA were found in the substantia nigra pars compacta and ventral tegmental area. Slight to moderate binding was found together with slight to moderate mRNA levels in the majority of neurons in the anterior olfactory nucleus; septum, especially medial septum and diagonal band of Broca; amygdala, especially basolateral amygdala; lateral habenula; ventromedial hypothalamic nucleus; lateral interpeduncular nucleus; central gray, dorsal cochlear nucleus; parabrachial nucleus; dorsal pontine tegmentum; pontine nuclei; commissural part of the nucleus tractus solitarius; inferior olive and dorsal horn of the spinal cord. In the cerebellum, very dense binding was found in the molecular layer together with slight mRNA levels in the majority of the granule cells and moderate mRNA levels in the basket and stellate cells. In conclusion, this study provides, for the first time, indirect assessment of the neurons containing cannabinoid receptor in the entire adult rat brain and will serve as a basis for future direct morphological confirmation using receptor immunohistochemistry and for functional studies.
Article
The main psychoactive component of marihuana, delta-9-tetrahydrocannabinol (THC) was injected into the 3rd cerebral ventricle. A single dose of THC (2 microliter of 10(-6) M) decreased serum LH temporarily but did not alter serum follicle-stimulating hormone (FSH) levels. The mediobasal hypothalamic (MBH) luteinizing hormone-releasing hormone (LHRH) content was elevated by 30 min after the injection. The elevation persisted for 1 h. Then, the LHRH content returned towards the preinjection level. In contrast, the LHRH in the organum vasculosum of the lamina terminalis did not change after a single dose of THC. The results indicate that THC alters pituitary LH release by inhibiting the release of LHRH which then increases in the MBH by continued synthesis or transport from rostral areas. In addition, the data support the existence of an FSH releasing factor, the release of which is not suppressed by this dose of THC. THC did not alter the release, storage or responsiveness to LHRH of cultured anterior pituitary cells, which further supports the view that its principal site of action is on the hypothalamus.
Article
The site of action of delta-9-tetrahydrocannabinol (THC) to inhibit the release of prolactin (PRL) and growth hormone (GH) was examined by in vivo and in vitro experiments. In conscious freely moving animals bearing implanted third ventricular (3V) and external jugular cannulae, THC or the diluent was microinjected into the 3V and blood samples were removed to determine the effect on plasma PRL and GH. Both the 0.4- and 4-micrograms dose injected intraventricularly resulted in a suppression of PRL and GH release as indicated by declines in plasma levels within 40-80 min which were highly significant statistically but not dose-related. The higher dose evoked a pulse of GH and/or PRL in most animals which preceded the lowering of hormonal levels. In the in vitro experiments dipersed anterior pituitary cells were incubated with 5 x 10(-8) or 5 x 10(-9)M THC or the diluent for 5 days. Fresh culture medium was added to the cells after 3 days and the cells cultured for an additional 2 days. After this period, the cells were incubated for an additional 2 h in culture medium with or without THC plus a near maximal dose of thyrotropin-releasing hormone and GH-releasing factor (50 and 10 ng/ml, respectively) or the diluent to evaluate the response of PRL and GH release, respectively. Neither dose of THC altered the release or storage of the two hormones during culture or affected the response to the releasing hormones which is suggestive that there is no direct effect of THC on either GH or PRL release.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
Article
This chapter focuses on the Δ'-tetrahydrocannabinol (Δ'-THC) and luteinizing hormone secretion. There is increasing evidence that the chronic administration of Δ'-THC produces central nervous effects somewhat different from those associated with acute treatment and further that the central effects of this agent may be because of hydroxylated metabolites. Thus it may be desirable in the future to compare the chronic effects of Δ'-THC and its metabolites with those of single doses upon endocrine regulation to appreciate the full endocrine consequences of exposure to marijuana. Despite the widespread use of marijuana, and some popular anecdotal reports of disturbances in menstrual cycling associated with the use of marijuana, there are no quantitative studies of the effect of this agent upon gonadotrophin secretion. Another possible mechanism of Δ'-THC effect that is to examine is the interaction with agents that act upon muscarinic receptors.
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