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NEUROPHARMACOLOGY
Center for Substance Abuse Research (K.B., M.Y., E.B.G., M.W.A.) and Departments of Microbiology and Immunology (J.J.M., T.K.E.) and Pharmacology (R.J.T.), Temple University School of Medicine, Philadelphia, Pennsylvania
Received August 30, 2006; accepted December 19, 2006.
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Abstract |
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; Elmquist et al., 1997), change in nociceptive threshold, and fever (Benamar et al., 2000, 2005; Abe et al., 2001). The fever due to LPS and other exogenous pyrogens is believed to be caused by the synthesis and release from monocytes and macrophages of a number of well characterized endogenous pyrogenic factors, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-
, and macrophage inflammatory protein-1 (Myers et al., 1994; Blatteis, 2006). In addition, it has been shown that the opioid system is involved in LPS-induced fever (Benamar et al., 2000, 2005) and that pretreatment with capsaicin, an agonist at the vanilloid receptor, blocks the first phase of LPS-induced fever (Dogen et al., 2004).
Cannabis and its derivative compounds, collectively known as cannabinoids, produce an array of pharmacological symptoms in animals and humans (Ovadia et al., 1995; Chaperon and Thiebot, 1999). Two subtypes of receptors, CB1 and CB2, mediate cannabinoid-induced effects (Howlett, 1995). The development of synthetic cannabinoid agonists has provided remarkable advances in cannabis research. One such ligand is the aminoalkylindole, (+)-WIN 55,212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], which displays high selectivity for cannabinoid receptors. Previous studies have demonstrated that WIN 55,212-2 is highly potent and efficacious in vivo and in vitro. WIN 55,212-2 prevents i.v. cocaine self-administration, increases tail-flick reflexes, exerts antihyperalgesic effects, and induces hypothermia in rats, indicating that WIN 55,212-2 is pharmacologically active in vivo (Fox et al., 2001). WIN 55,212-2 undergoes less nonspecific binding than classical cannabinoids and interacts negligibly with other neurotransmitter systems and ion channels (Jansen et al., 1992). In contrast, 
9-tetrahydrocannabinol (9-THC) has been reported to produce hypothermia by interacting with other neurotransmitters, including serotonin (Davies and Graham, 1980). One of the major advances in CB research has been the development of a potent and selective antagonist of the CB1 receptor, SR141716A. This compound was found to block the hypokinetic, hypothermic, cataleptic, and antinociceptive effects of 9-THC and WIN 55,212-2 in mice and rats (Rinaldi-Carmona et al., 1994; Reche et al., 1996). In addition, studies with SR141716 have provided evidence for the presence of CB1 receptors in peripheral tissues as well as in the central nervous system (Varga et al., 1995; Lake et al., 1997).
However, the CB2 receptor subtype has been defined as the peripheral CB receptor, primarily because CB2 mRNA expression has been detected mainly in cells of the immune system (Galieque et al., 1995). The CB2 is expressed inducibly and is present at high levels compared with the CB1 when microglia are in responsive and primed states of activation (Cabral and Marciano-Cabral, 2005). Like the CB1 receptor subtype, the CB2 receptor is a member of the G protein-coupled receptor family and on stimulation causes inhibition of adenylyl cyclase. A potent, selective, and orally active antagonist of the CB2 receptor, SR144528 was recently identified and shown to have a 700-fold higher affinity for the CB2 receptor than for the CB1 receptor (Rinaldi-Carmona et al., 1998).
Because the cannabinoids and LPS both affect the immune and thermoregulatory systems, an investigation was undertaken to determine whether the cannabinoids affect the development of fever after systemic injection by LPS. In this present study, the in vivo effects of two cannabinoid agonists, 9-THC (main psychoactive constituent of marijuana) and WIN 55,212-2 (synthetic cannabinoid agonist), were examined for effects on LPS-induced fever. Highly selective CB receptor antagonists SR141716 and SR144528 were used in an attempt to identify the receptor subtype(s) through which WIN 55,212-2 mediates its effects on LPS-induced fever.
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Materials and Methods |
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Surgery Procedures. Rats were anesthetized with an i.p. injection of a mixture of ketamine hydrochloride (80 mg/kg) and acepromazine maleate (0.2 mg/kg). An incision 2 cm in length was made along the linea alba, and the underlying tissue was dissected and retracted. A transmitter (Mini-Mitter, Sunriver, OR) was then inserted in the i.p. space. After the transmitter was passed through the incision, the abdominal musculature and dermis were sutured independently (Benamar et al., 2002). The animals were returned to individual cages in the environmental room.
Body Temperature Measurement. One week after surgery, the rats were tested in an environmental room (Hotpack), maintained at 21 ± 0.3°C ambient temperature and 52 ± 2% relative humidity. After 1 h of adaptation, two readings at 15-min intervals were averaged to determine the baseline. Either saline or drug was then injected i.p. Tb was measured by a biotelemetry system (Mini-Mitter) using calibrated transmitters implanted i.p. Signals from the transmitter were delivered through a computer-linked receiver. This method minimizes stress to animals during the Tb reading. Thus, the Tb could be monitored continuously and recorded without restraint or any disturbance to the animal. All experiments were started between 9:00 and 10:00 AM to minimize the effect of circadian variation in Tb.
Enzyme-Linked Immunosorbent Assay. The concentration of IL-6 in the plasma was determined by using an enzyme-linked immunosorbent assay kit from R&D Systems (Minneapolis, MN). The assay was performed according to the manufacturer's instructions. At selected time points after i.p. injection of vehicle/LPS or WIN 55,212-2/LPS, rats were killed for collection of blood. Blood samples were immediately centrifuged for measurement of IL-6 in the plasma.
Drugs. The cannabinoid agonist, WIN 55,212-2, and its inactive enantiomer, WIN 55,212-3, were obtained from Sigma-Aldrich (St. Louis, MO). 9-THC, SR1411716A, and SR144528 were supplied by the National Institute on Drug Abuse (Rockville, MD). These drugs were dissolved in Cremophor, dimethyl sulfoxide, and saline (1:1:18). Lipopolysaccharide was the phenol-extracted preparation of Escherichia coli (0111:B4) and was obtained from Sigma-Aldrich and dissolved in pyrogen-free saline.
Statistical Analysis. All results were expressed as mean ± S.E.M. Statistical analysis of differences between groups was determined by analysis of variance followed by Tukey's test. A value of p less than 0.05 was considered statistically significant.
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Results |
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The Effect of WIN 55,212-2 on LPS-Induced Fever. In Fig. 1, LPS injected i.p. (50 µg/kg) induced an increase in Tb that peaked at 180 min (1.25 ± 0.27°C) and again at 5 h (1.52 ± 0.21°C), in agreement with our previous study (Benamar et al., 2000). To determine whether a cannabinoid receptor agonist would interfere with the LPS-induced fever, WIN 55,212-2 (0.5–1.5 mg/kg) was injected 30 min before LPS (Fig. 1). WIN 55,212-2, at a dose of 0.5 mg/kg, did not affect the LPS-induced fever. The LPS-induced fever was partially attenuated by WIN 55,212-2 at a dose of 1 mg/kg (Fig. 1, p < 0.05) and further reduced at a dose of 1.5 mg/kg WIN 55,212-2. Mean Tb before injection was 37.61 ± 0.15°C for the vehicle/LPS group, 37.64 ± 0.19°C for the WIN 55,212-2 (0.5 mg/kg)/LPS group, 37.60 ± 0.17°C for the WIN 55,212-3 (1 mg/kg)/LPS group, 37.87 ± 0.23°C for the WIN 55,212-2 (1.5 mg/kg) group, and 37 ± 14°C for vehicle/saline group.
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Effect of WIN 55,212-3 (Inactive Form) on LPS-Induced Fever. To confirm that WIN55,212-2 functions through the cannabinoid receptor, we tested whether an inactive enantiomer of the aminoalkylindole could affect LPS-induced fever. WIN 55,212-3 (1.5 mg/kg) had no effect on Tb compared with vehicle (Fig. 2, p > 0.05). Moreover, pretreatment with this inactive form did not alter the LPS-induced fever (Fig. 2, p > 0.05). Mean Tb before injection was 37.77 ± 0.11°C for the vehicle/LPS group, 37.67 ± 0.14°C for the WIN 55,212-3/LPS group, 37.65 ± 0.09°C for the WIN 55,212-3/vehicle and group, and 37.62 ± 0.24°C for the vehicle/saline group.
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Antagonism of WIN 55,212-2 Effect on LPS-Induced Fever by SR141716. To determine the contribution of CB1 receptors in the WIN 55,212-2 effect on LPS-induced fever, SR141716 was administered to rats 30 min before the WIN 55,212-2 and 1 h before LPS (50 µg/kg). SR141716 2.5 (mg/kg i.p.) was found to block the antagonistic effect of WIN 55,212-2 (1.5 mg/kg) on LPS-induced fever (Fig. 3, p < 0.05). Neither the SR141716/vehicle/saline nor vehicle/vehicle/saline group showed an effect on Tb. The mean Tb before injection was 37.44 ± 0.18°C for the vehicle/vehicle/LPS group, 37.59 ± 0.11°C for the SR141716/WIN 55,212-2/LPS group, 37.62 ± 0.06°C for the vehicle/WIN 55,212-2/vehicle, 37.56 ± 0.14°C.
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Effects of SR141716 or SR144528 on LPS-Induced Fever. In separate experiments, we also determined whether CB1 or CB2 receptor antagonists themselves affected the LPS-induced fever. SR141716 or SR144528 was injected 30 min before LPS. SR141716 (2.5 mg/kg) completely abolished the fever produced by LPS (Fig. 5, p < 0.05). In contrast, SR144528 2.5 mg/kg did not alter LPS-evoked fever (Fig. 6, p > 0.05). Neither SR141716 nor SR144528 significantly affected baseline temperatures (Figs. 5, 6, 7), suggesting that the endocannabinoid system does not tonically regulate Tb. Mean Tb before injection was 37.76 ± 0.08°C for the vehicle/LPS group, 37.74 ± 0.15°C for the SR141176A/LPS group, 37.67 ± 0.23°C for the SR141716/vehicle, 37.69 ± 0.15°C for the vehicle/saline group, 37.63 ± 0.13°C for the SR144528/LPS group, 37.66 ± 0.2°C for the SR144528 (2.5 mg/kg) group, 37.59 ± 0.17°C for the SR144528 (1 mg/kg) group, and 37.71 ± 0.21°C for the SR144528 (5 mg/kg) group. The doses of SR141716 and SR144528 were chosen for these studies based on our previous data (Rawls et al., 2002).
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WIN 55,212-2 Blocks LPS-Induced Increases in IL-6 Levels in Plasma. To test whether inflammatory cytokine levels were effected by this cannabinoid treatment, we determined the levels of plasma IL-6 following cannabinoid addition. LPS induced a significant increase in plasma IL-6 at levels 2 and 4 h postinjection of LPS (Fig. 8). WIN 55,212-2 given 30 min before LPS significantly attenuated the increase in the levels of IL-6 at the 3- and 5-h time points. Neither WIN 55,212-2 by itself nor vehicle affected significantly the levels of IL-6 (data not shown).
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The Effect of 9-THC on Body Temperature and on LPS-Induced Fever. To ensure that the ability of cannabinoids to modulate LPS-induced fever was not limited to the aminoalkylindole WIN 55,212-2, we carried out similar experiments using the chemically unique 9-THC. The i.p. injection of 9-THC at doses of 0.5 or 1 mg/kg did not significantly affect the Tb relative to vehicle (Table 2, p > 0.05). However, a higher dose of 9-THC (1.5 mg/kg) produced significant hypothermia compared with control (p < 0.05).
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The LPS-induced fever showed a trend toward reduction by 9-THC at a dose of 0.5 mg/kg (Fig. 9) and significantly reduced at a dose of 1 mg/kg (Fig. 9, p < 0.05). Mean Tb before injection was 37.64 ± 0.12°C for the vehicle/LPS group, 37.71 ± 0.21°C for the 9-THC (0.5 mg/kg)/LPS group, and 37.55 ± 0.23°C for the 9-THC (1 mg/kg)/LPS group.
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Discussion |
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9-THC. This agonist at doses of 0.5 or 1 mg/kg also attenuated LPS-induced fever.
It has been demonstrated that circulating levels of IL-6 rise dramatically following LPS injection with a profile that correlates closely with the development of fever (Harre et al., 2002) and that the neutralization of endogenous IL-6 (Cartmell et al., 2000) or absence of IL-6 in knockout mice (Chai et al., 1996) results in an almost total inhibition of the LPS-induced fever, suggesting that IL-6 is an essential circulating mediator of the brain-derived fever response. In an attempt to investigate the involvement of this inflammatory cytokine in the inhibitory effect of WIN 55,212-2 on LPS-induced fever, we determined the effect of WIN 55,212-2 on plasma levels of IL-6 induced by LPS, examined concurrently at two different time points that coincide with the first (3 h) and second (5 h) peaks of LPS-induced fever. In parallel with the inhibitory effect of WIN 55,212-2 on LPS-induced fever, the plasma level of IL-6 was also attenuated at both time points. Several studies have reported the immunosuppressive effect of cannabinoids on peripheral circulating cytokines, including TNF-, IL-10, IL-12, IL-6, and IL-1
(Gallily et al., 1997; Smith et al., 2000; Roche et al., 2006). HU210 fully attenuated the LPS-induced increase in the levels of IL-1, TNF-, and IL-6, and changes in cytokine levels were accompanied by reduced circulating lymphocyte numbers and increased plasma corticosterone levels in response to acute administration of LPS and/or cannabinoid drugs (Roche et al., 2006). 9-THC and WIN 55,212-2 were investigated for their effects on LPS-induced bronchopulmonary inflammation in mice (Berdyshev et al., 1998). Both drugs were found to cause a dose-related decrease in TNF- in bronchoalveolar lavage fluids. The effect of WIN 55,212-2 on LPS-induced serum cytokine responses has been also investigated in mice. The levels of TNF-, IL-12, IL-1, and IL-6 were reduced in mice pretreated with WIN 55,212-2 (Smith et al., 2000). The mechanism by which WIN 55,212-2 produces its effect on LPS-induced fever is unknown. The fact that cytokines, such as IL-6, act as endogenous pyrogens and play an important role in the mechanisms responsible for the development of the febrile response during infection and inflammation (Kluger et al., 1995) and that cannabinoids have immunosuppressive effects may provide an explanation for our results. WIN 55,212-2, by diminishing the IL-6 production by LPS, may cause a reduction in LPS-induced fever. Of course, this explanation does not dismiss the possible implication of other mediators of fever, other cytokines (e.g., interleukin-1), and/or chemokines.
The WIN 55,212-2 effects on LPS-induced fever could occur through the CB1 and/or CB2 receptors. CB1 receptors are located primarily in the central nervous system and are thought to mediate the central effects of cannabinoids (Howlett, 1995). CB1 receptor immunoreactivity has been detected in the hypothalamus (Tsou et al., 1998), including the lateral hypothalamic area and the preoptic anterior hypothalamus, the primary area implicated in body temperature regulation (Moldrich and Wenger, 2000). In contrast, CB2 receptors are expressed mainly in the peripheral immune cells (Dragic et al., 1996). CB2 receptor mRNA has been found in spleen, tonsils, and thymus, which are the major tissues of immune cell production and regulation (Cabral and Pettit, 1998). However, recent evidence shows the expression of CB2 receptor mRNA and protein localization on brainstem neurons and microglia (Cabral and Marciano-Cabral, 2005; Van Sickle et al., 2005). The present study shows that SR141716 prevented the WIN 55,212-2 effects on LPS-induced fever, indicating that a CB1 receptor mechanism mediated the response. The blockade by SR141716 of WIN 55,212-2 effects in the present study is consistent with previous reports. For example, SR141716 blocked cannabinoid agonist-induced hypothermia in rats (Rawls et al., 2002). Several lines of evidence implicate the involvement of cannabinoids, acting via cannabinoid CB1 receptors, in the action of LPS in the rat (Varga et al., 1998). The systemic administration of a selective CB1 receptor antagonist SR141716 protects rats against hypotension induced by bacterial LPS (Varga et al., 1998), and in the initial phase of septic shock induced by LPS, the activation of CB1 receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response (Godlewski et al., 2004). CB1 receptors contribute to the immunosuppressive effects of HU210, both centrally and peripherally, since SR141716 attenuated, albeit partially, the decrease in LPS-induced cytokine release induced by this cannabinoid receptor agonist (Roche et al., 2006). Because cytokines are released in response to LPS, and the CB2 receptor has a modulatory role in the immune system, including the cytokine network (Klein et al., 1998), it was tempting to assume that CB2 receptors might contribute to the LPS-induced fever as well. In contrast to SR141716, the present study shows that SR144528 did not affect the inhibitory effects of WIN 55,212-2 on LPS-induced fever, indicating that the thermoregulatory interaction between WIN 55,212-2 and LPS is insensitive to CB2 receptor activation.
An unexpected finding in the present study was the ability of SR141716 itself to attenuate LPS-induced fever. Its effect on LPS-induced fever was similar to that of WIN 55,212-2 and LPS. Interestingly, the LPS-induced cytokines can be modulated by CB agonists through activation of the CB1 receptors in mice (Smith et al., 2000). The decreases in serum TNF- and IL-12 that occurred in cannabinoid-agonist-treated mice could be blocked by SR141716 but not by SR144528 (Smith et al., 2000). SR141716 itself modulated LPS-induced cytokine responses, and its effects on inflammatory cytokine responses and anti-inflammatory IL-10 were qualitatively similar to those of the CB agonist WIN 55,212-2, suggesting that cytokine modulation by SR141716 seems to be a result of partial agonism (Smith et al., 2000). Several lines of evidence suggest that SR141716, initially characterized as the first potent and selective cannabinoid CB1 receptor antagonist (Rinaldi-Carmona et al., 1994), also has inverse agonist properties. The evidence mainly comes from biochemical studies regarding adenylate cyclase and mitogen-activated protein kinase activity in heterologous expression systems (Bouaboula et al., 1997). The administration of SR141716 alone was sufficient to suppress central and peripheral cytokine responses, in a manner qualitatively and quantitatively similar to the immunosuppressive effects of HU210 (Roche et al., 2006). It is possible that such an effect may occur with SR141716 and LPS-induced fever. In these studies, we also determined whether CB2 receptors are implicated directly in LPS-induced fever. In contrast to SR141716, SR144528 did not influence the development of fever evoked by LPS. In agreement with our previous studies (Rawls et al., 2002), neither SR141716 nor SR144528 by itself altered Tb, suggesting that the endocannabinoid system does not tonically modulate Tb. The present report presents a novel role for cannabinoids by demonstrating a thermoregulatory interaction between cannabinoids and LPS and showing that cannabinoid ligands can prevent the development of fever induced by systemic LPS administration.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: Tb, body temperature; LPS, lipopolysaccharide; IL, interleukin; (+)-WIN 55,212-2, (4,5-dihydro-2-methyl-4(4-morpholinyl-methyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one; 9-THC, 9-tetrahydrocannabinol; SR141716, N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride; SR144528, N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl]5-(4-choro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide; WIN 55,212-3, S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthanlenyl)methanone mesylate; CB, cannabinoid.
Address correspondence to: Dr. Khalid Benamar, Center of Substance Abuse Research, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140. E-mail: kbenamar{at}temple.edu
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