Biomedical subjects

Martin W Adler

Publications and source records attributed to Martin W Adler.

At least 19 recordsLinked to original sources

PubMed2006

A novel role of cannabinoids: implication in the fever induced by bacterial lipopolysaccharide.

There is continuing interest in elucidating the actions of drugs of abuse on the immune system and on infection. The present study investigated the effects of the cannabinoid (CB) receptor agonist 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], on fever produced after injection of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, the best known and most frequently used experimental model. Intraperitoneal injection of LPS (50 mug/kg) induced a biphasic fever, with the first peak at 180 min and the second at 300 min postinjection. Pretreatment with a nonhypothermic dose of the cannabinoid receptor agonist WIN 55,212-2 (0.5-1.5 mg/kg i.p.) antagonized the LPS-induced fever. However, pretreatment with the inactive enantiomer WIN 55,212-3 [1.5 mg/kg i.p.; S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthanlenyl)methanone mesylate] did not. The inhibitory effect of WIN 55,212-2 on LPS-induced fever was reversed by SR141716 [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride], a selective CB1 receptor antagonist, but not by 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), a selective antagonist at the CB2 receptor. The present results show that cannabinoids interact with systemic bacterial LPS injection and indicate a role of the CB1 receptor subtype in the pathogenesis of LPS fever.

Animals↗

PubMed2006

Nociceptin/orphanin FQ blocks the antinociception induced by mu, kappa and delta opioid agonists on the cold water tail-flick test.

Nociceptin/orphanin FQ (N/OFQ), a 17-amino-acid peptide, is an endogenous agonist whose receptor is similar in sequence to mu, delta and kappa opioid receptors. It has been reported that N/OFQ can block antinociceptive effects induced by opioid receptor agonists in the radiant heat tail-flick test and warm water tail-withdrawal test. The present study was designed to see the effect of N/OFQ on antinociception induced by opioid receptor agonists in the cold water tail-flick (CWT) test, which measures a different type of pain. In adult male Sprague-Dawley (S-D) rats given subcutaneous (s.c.) injections of saline or morphine (8 mg/kg), intracerebroventricular (i.c.v.) injection of N/OFQ (18 microg) 15 min later produced a significant reversal of morphine antinociception (P<0.01, ANOVA followed by Duncan's test), compared to the corresponding saline control group. Saline (t=+15 min, i.c.v.) had no effect on s.c. morphine antinociception (P>0.01), compared to the corresponding saline control group. When the kappa opioid receptor agonist spiradoline (80 mg/kg, s.c.) was used instead of morphine, similar results were observed. In another series of experiments, it was found that i.c.v. injection of N/OFQ (18 microg) reversed the antinociception induced by i.c.v. injection of the selective mu opioid agonist PL017 (2 microg), delta opioid agonist DPDPE (50 ng) and kappa opioid agonist dynorphin (21.5 microg), respectively. These results indicate that N/OFQ may be an endogenous anti-opioid peptide in the brain of rats in the CWT test.

Analgesics, Opioid↗

PubMed2006

Rapid heterologous desensitization of antinociceptive activity between mu or delta opioid receptors and chemokine receptors in rats.

Previous studies have shown pretreatment with chemokines CCL5/RANTES (100 ng) or CXCL12/SDF-1alpha (100 ng) injected into the periaqueductal grey (PAG) region of the brain, 30 min before the mu opioid agonist DAMGO (400 ng), blocked the antinociception induced by DAMGO in the in vivo cold water tail-flick (CWT) antinociceptive test in rats. In the present experiments, we tested whether the action of other agonists at mu and delta opioid receptors is blocked when CCL5/RANTES or CXCL12/SDF-1alpha is administered into the PAG 30 min before, or co-administered with, opioid agonists in the CWT assay. The results showed that: (1) CXCL12/SDF-1alpha (100 ng, PAG) or CCL5/RANTES (100 ng, PAG), given 30 min before the opioid agonist morphine, or selective delta opioid receptor agonist DPDPE, blocked the antinociceptive effect of these drugs; (2) CXCL12/SDF-1alpha (100 ng, PAG) or CCL5/RANTES (100 ng, PAG), injected at the same time as DAMGO or DPDPE, significantly reduced the antinociceptive effect induced by these drugs. These results demonstrate that the heterologous desensitization is rapid between the mu or delta opioid receptors and either CCL5/RANTES receptor CCR5 or CXCL12/SDF-1alpha receptor CXCR4 in vivo, but the effect is greater if the chemokine is administered before the opioid.

Analgesics, Opioid↗

PubMed2006

Effects of mu, kappa or delta opioids administered by pellet or pump on oral Salmonella infection and gastrointestinal transit.

Our laboratory has shown previously that subcutaneously implanted, slow-release morphine pellets markedly enhanced susceptibility to oral infection with Salmonella typhimurium. Further, morphine, kappa and delta opioid receptor agonists infused via osmotic minipumps were immunosuppressive. The present study compared morphine pellets to morphine pumps and also examined the differential effects of morphine versus U50,488H (kappa agonist), deltorphin II (delta2 agonist), and (D-Pen2, D-Pen5)-enkephalin (DPDPE, delta1 agonist), administered via Alzet minipumps, on oral Salmonella infection and on gastrointestinal transit. The results show that all morphine-pelleted mice (26/26) had a marked increase in Salmonella burden in the Peyer's Patches, mesenteric lymph nodes and spleen. In comparison, only 8/20 mice receiving morphine by minipump at doses ranging from 1 to 25 mg/kg/day had any culturable Salmonella in their organs and the number of bacteria was very low. The level of Salmonella colonization correlated with blood morphine levels and gut transit measured using an intragastric charcoal meal. Morphine pellets inhibited gut transit by 38%, while mice receiving morphine by minipump at doses of 1 to 25 mg/kg/day showed only a dose-dependent 7% to 17% inhibition. Mice receiving various doses of U50,488H or DPDPE had no culturable Salmonella in the three sites. Deltorphin II given by minipump resulted in a moderate level of Salmonella in the spleen. Deltorphin II and U50,488H (0.1 to 10 mg/kg/day) did not suppress gut transit. The present studies indicate that a predominantly mu opioid receptor agonist, morphine, given by slow-release pellet, potentiated Salmonella infection and inhibited gastrointestinal transit. In contrast, morphine in pumps slightly inhibited intestinal transit, but did not sensitize to Salmonella infection. A delta1 opioid receptor agonist did not sensitize to infection, and a delta2 and a kappa opioid receptor agonist had minimal effects on either parameter.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2006

Viewing chemokines as a third major system of communication in the brain.

There is irrefutable proof that opioids and other classes of centrally acting drugs have profound effects on the immune system. Evidence is mounting that products of the immune system, such as chemokines, can reciprocally alter the actions of these drugs and the endogenous ligands for their receptors. Chemokines are a family of small (8 to 12 kDa) proteins involved in cellular migration and intercellular communication. With a few exceptions, they act on more than one receptor. Although the chemokines and their G protein-coupled receptors are located in both glia and neurons throughout the brain, they are not uniformly distributed. They are found in such brain areas as the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. Among the chemokines differentially localized in brain neurons and glia are CCL2/MCP-1, CXCL12/SDF-1alpha, CX3CL1/fractalkine, CXCL10/IP 10, CCL3/MIP-1alpha, and CCL5/RANTES. Functional roles for the chemokine system, composed of the chemokine ligands and their receptors, have been suggested in brain development and heterologous desensitization. The system can alter the actions of neuronally active pharmacological agents such as opioids and cannabinoids and interact with neurotransmitter systems. In this review, we propose that the endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. It can thus be thought of as the third major system in the brain.

Animals↗

PubMed2006

Morphine withdrawal lowers host defense to enteric bacteria: spontaneous sepsis and increased sensitivity to oral Salmonella enterica serovar Typhimurium infection.

Understanding the consequences of drug withdrawal on immune function and host defense to infection is important. We, and others, previously demonstrated that morphine withdrawal results in immunosuppression and sensitizes to lipopolysaccharide-induced septic shock. In the present study, the effect of morphine withdrawal on spontaneous sepsis and on oral infection with Salmonella enterica serovar Typhimurium was examined. Mice were chronically exposed to morphine for 96 h by implantation of a slow-release morphine pellet. Abrupt withdrawal was induced by removal of the pellet. In the sepsis model, bacterial colonization was examined and bacterial species were identified by necropsy of various tissues. It was found that at 48 h postwithdrawal, morphine-treated mice had enteric bacteria that were detected in the Peyer's patches (4/5), mesenteric lymph nodes (4/5), spleens (4/10), livers (6/10), and peritoneal cavities (8/10). In placebo pellet-withdrawn mice, only 2/40 cultures were positive. The most frequently detected organisms in tissues of morphine-withdrawn mice were Enterococcus faecium followed by Klebsiella pneumoniae. Both organisms are part of the normal gastrointestinal flora. In the infection model, mice were orally inoculated with S. enterica 24 h post-initiation of abrupt withdrawal from morphine. Withdrawal significantly decreased the mean survival time and significantly increased the Salmonella burden in various tissues of infected mice compared to placebo-withdrawn animals. Elevated levels of the proinflammatory cytokines were observed in spleens of morphine-withdrawn mice, compared to placebo-withdrawn mice. These findings demonstrate that morphine withdrawal sensitizes to oral infection with a bacterial pathogen and predisposes mice to bacterial sepsis.

Animals↗

PubMed2005

The dynamic relationship between mu and kappa opioid receptors in body temperature regulation.

Previous studies demonstrated that intracerebroventricular (icv) injection of a kappa opioid receptor agonist decreased, and a mu agonist increased, body temperature (Tb) in rats. A dose-response study with the selective kappa antagonist nor-binaltorphimine (nor-BNI) showed that a low dose (1.25 nmol, icv) alone had no effect, although a high dose (25 nmol, icv) increased Tb. It was hypothesized that the hyperthermia induced by nor-BNI was the result of the antagonist blocking the kappa opioid receptor and releasing its inhibition of mu opioid receptor activity. To determine whether the Tb increase caused by nor-BNI was a mu receptor-mediated effect, we administered the selective mu antagonist CTAP (1.25 nmol, icv) 15 min after nor-BNI (25 nmol, icv) and measured rectal Tb in unrestrained rats. CTAP significantly antagonized the Tb increase induced by icv injection of nor-BNI. Injection of 5 or 10 nmol of CTAP alone significantly decreased the Tb, and 1.25 nmol of nor-BNI blocked that effect, indicating that the CTAP-induced hypothermia was kappa-mediated. The findings strongly suggest that mu antagonists, in blocking the basal hyperthermia mediated by mu receptors, can unmask the endogenous kappa receptor-mediated hypothermia, and that there is a tonic balance between mu and kappa opioid receptors that serves as a homeostatic mechanism for maintaining Tb.

Animals↗

PubMed2005

Splenic macrophages and B cells mediate immunosuppression following abrupt withdrawal from morphine.

We have previously shown that abrupt withdrawal (AW) from morphine induces greater than 80% immunosuppression in murine spleen cells, as assessed by the capacity to mount an in vitro plaque-forming cell response to sheep red blood cells. Present studies about the mechanisms of immunosuppression following AW showed that addition of highly enriched (CD11b+) splenic macrophages (obtained by cell sorting or magnetic separation) from AW mice to cultures of normal, unfractionated spleen cells suppressed immune responses. Further, addition of highly enriched (CD19+) B cells (but not T cells) from AW mice to normal cells was also immunosuppressive. B cells from AW mice were also able to inhibit the proliferative response of normal spleen cells to concanavalin A but not to lipopolysaccharide. Overall, the data suggest that immunosuppression by AW spleen cells is a result of active suppression by macrophages and B cells.

Acute Disease↗

PubMed2005

Are chemokines the third major system in the brain?

Chemokines are a family of small proteins involved in cellular migration and intercellular communication. Although the chemokines and their receptors are located throughout the brain, they are not distributed uniformly. Among the chemokines and their receptors that are arrayed disproportionately in glia and neurons are monocyte chemotactic protein-1/CC chemokine ligand 2 (CCL2), stromal cell-derived factor-1/CXC chemokine ligand 12 (CXCL12), fractalkine/CX3C chemokine ligand 1, interferon-gamma-inducible-protein-10/CXCL10, macrophage inflammatory protein-1alpha/CCL3, and regulated on activation, normal T cell expressed and secreted/CCL5. In the brain, they are found in the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. The uneven distribution suggests that there may be functional roles for the chemokine "system," comprised of chemokine ligands and their receptors. In addition to anatomical, immunohistochemical, and in vitro studies establishing the expression of the chemokine ligands and receptors, there is an increasing body of research that suggests that the chemokine system plays a crucial role in brain development and function. Our data indicate that the chemokine system can alter the actions of neuronally active pharmacological agents including the opioids and cannabinoids. Combined with evidence that the chemokine system in the brain interacts with neurotransmitter systems, we propose the following hypothesis: The endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. The chemokine system can thus be thought of as the third major transmitter system in the brain.

Animals↗

PubMed2005

Morphine withdrawal sensitizes mice to lipopolysaccharide: elevated TNF-alpha and nitric oxide with decreased IL-12.

Mice made dependent on morphine using slow-release morphine pellets for 96 h were withdrawn by removal of pellets, followed by a sublethal dose of LPS 24 h later. These animals exhibited 100% lethality. Animals withdrawn from placebo pellets receiving LPS all survived, as did morphine-withdrawn mice receiving saline. Morphine-withdrawn LPS-treated animals had elevated serum TNF-alpha and nitric oxide levels, and depressed IL-12 levels compared to controls. Anti-TNF-alpha antibody given prior to LPS challenge afforded significant protection to morphine-withdrawn animals. These studies show that morphine withdrawal sensitizes to LPS lethality via increased production of TNF-alpha.

Animals↗

PubMed2005

Unresponsiveness of mu-opioid receptor knockout mice to lipopolysaccharide-induced fever.

Recently, we demonstrated that lipopolysaccharide (LPS)-induced fever could be suppressed by a selective mu-opioid receptor antagonist, indicating that the mu-opioid system is involved in the LPS fever. In the present study, to confirm the role of the mu-opioid system in the pathogenesis of LPS fever, we used mice lacking the mu-opioid receptor. In the wild type (WT), following intraperitoneal (i.p.) injection of 100 microg kg(-1) of LPS, body temperature (T(b)) increased approximately 1 degrees C and remained elevated during the 360-min recording period. In the mu-opioid receptor knockout (MOR-KO) mice, the administration of 100 microg kg(-1) i.p. of LPS did not induce fever during the recording period. Saline by itself, given i.p., did not alter the T(b), either in WT or MOR-KO. These results confirm that the mu-opioid system is involved in LPS-induced fever.

Animals↗

PubMed2005

Increased sensitivity to Salmonella enterica serovar Typhimurium infection in mice undergoing withdrawal from morphine is associated with suppression of interleukin-12.

We have shown previously that withdrawal from morphine induces immunosuppression in mice. The present study reports the effects of morphine withdrawal on infection with Salmonella enterica serovar Typhimurium. Mice were made dependent on morphine by the implantation of a slow-release morphine pellet for 96 h. Controls received a placebo pellet. Withdrawal was induced by pellet removal. Mice were inoculated intraperitoneally with Salmonella 24 h postwithdrawal. Morphine withdrawal sensitized mice to Salmonella infection, as evidenced by increased mortality, shortened mean survival time, and increased bacterial load in the blood, spleen, and liver. Examination of the levels of a panel of proinflammatory cytokines in sera of infected, morphine-withdrawn mice showed that morphine withdrawal inhibited the elevation of interleukin-12p70 (IL-12p70). The production of IL-12p40 in morphine withdrawal mice was also suppressed. The administration of exogenous IL-12 significantly decreased the bacterial burden in morphine-withdrawn mice. These studies show a correlation between the suppression of IL-12 production and a heightened susceptibility to Salmonella infection in mice undergoing withdrawal from morphine.

Animals↗

PubMed2004

Intrahypothalamic injection of deltorphin-II alters body temperature in rats.

The present study investigated the effect of H-Try-d-Ala-Phe-Glu-Val-Gly-NH2 deltorphin-II, a selective delta-2 agonist, and [d-Pen(2),d-Pen(5)]enkephalin, a selective delta-1 agonist, on body temperature in the rat. Microinjected into the preoptic anterior hypothalamus (POAH), deltorphin-II (0.1-1 microg) produced an immediate dose-related hyperthermia following injection. Injection of the delta-2 antagonist naltriben into the preoptic anterior hypothalamus (1 microg, 30 min prior to deltorphin-II) significantly attenuated the deltorphin-II-induced hyperthermia. Microinjection of [d-Pen(2),d-Pen(5)]enkephalin into the POAH (0.1-3 microg) did not affect Tb. The data demonstrate that delta-2 receptors are involved in the mediation of Tb effects, and deltorphin-II exerts its action directly on thermosensitive cells of the preoptic anterior hypothalamus. Delta-1 opioid receptors do not appear to be involved in the control of body temperature.

Animals↗

PubMed2004

Paradoxes of immunosuppression in mouse models of withdrawal.

Previously, our laboratory showed that either abrupt (AW) or precipitated withdrawal (PW) from morphine led to profound suppression of murine splenic antibody responses to sheep red blood cells at 24 h post-withdrawal. In the present studies, we examined the immune mechanisms mediating suppression at that time point. A co-culture method was used to examine whether cells from withdrawn mice had (1) a deficit in function and/or (2) contained populations of suppressor cells. To examine the first hypothesis, cells from normal mice were co-cultured with cells from withdrawn mice in a 1:3 ratio (normal/withdrawn). To test the second hypothesis, the ratio was reversed. The results were paradoxical. Co-culture of cells in a 1:3 ratio showed that spleen cells from withdrawn mice had a deficit in macrophage function. Spleen cells from withdrawn mice also showed decreased mRNA levels of IL-1beta, IL-1-Ra, and TNF-alpha and a suppression of co-stimulatory molecule expression. To examine the second hypothesis, cells were co-cultured in a 3:1 ratio (normal/withdrawn). In this paradigm, spleen cells from abrupt withdrawn mice were shown to contain populations of both suppressor macrophages and B-cells. In vivo experiments carried out on mice 24 h post-withdrawal showed increased sensitivity to the lethal effects of LPS and increased production of TNF-alpha, implying a state of macrophage activation. Thus evidence for both suppressed and activated macrophages has been obtained in mice 24 h after abrupt withdrawal from morphine.

Animals↗

PubMed2004

GABAA receptors modulate cannabinoid-evoked hypothermia.

Cannabinoids evoke hypothermia by stimulating central CB(1) receptors. GABA induces hypothermia via GABA(A) or GABA(B) receptor activation. CB(1) receptor activation increases GABA release in the hypothalamus, a central locus for thermoregulation, suggesting that cannabinoid and GABA systems may be functionally linked in body temperature regulation. We investigated whether GABA receptors modulate the hypothermic actions of [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one] (WIN 55212-2), a selective cannabinoid agonist, in male Sprague-Dawley rats. WIN 55212-2 (2.5 mg/kg im) produced a rapid hypothermia that peaked 45-90 min postinjection. The hypothermia was attenuated by bicuculline (2 mg/kg ip), a GABA(A) antagonist. However, SCH 50911 (1-10 mg/kg ip), a GABA(B) blocker, did not antagonize the hypothermia. Neither bicuculline (2 mg/kg) nor SCH 50911 (10 mg/kg) by itself altered body temperature. We also investigated a possible role for CB(1) receptors in GABA-generated hypothermia. Muscimol (2.5 mg/kg ip), a GABA(A) agonist, or baclofen (5 mg/kg ip), a GABA(B) agonist, evoked a significant hypothermia. Blockade of CB(1) receptors with SR141716A (2.5 mg/kg im) did not antagonize muscimol- or baclofen-induced hypothermia, indicating that GABA-evoked hypothermia does not contain a CB(1)-sensitive component. Our results implicate GABA(A) receptors in the hypothermic actions of cannabinoids and provide further evidence of a functional link between cannabinoid and GABA systems.

Animals↗

PubMed2004

Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model.

Multiple sclerosis (MS) is the most common of the immune demyelinating disorders of the central nervous system (CNS). Leukocyte/endothelial interactions are important steps in the progression of the disease and substances that interfere with these activities have been evaluated as potential therapeutic agents. Cannabinoid receptor agonists have been shown to downregulate immune responses and there is preliminary evidence that they may slow the progress of MS. The purpose of this investigation was to determine how cannabinoid receptor agonists interfere with leukocyte rolling and adhesion. This was investigated in an experimental autoimmune encephalomyelitis (EAE) model using six to eight week old C57BL/6 mice. Mouse myelin oligodendrocyte protein and pertussis toxin were used to induce EAE. WIN 55212-2, CB1 and CB2 antagonist were given. By use of in vivo intravital microscopy, leukocyte/endothelial interactions were evaluated via a cranial window implanted two days before. The results demonstrated that EAE increases leukocyte rolling and firm adhesion in the brain, and that this increased leukocyte/endothelial interaction can be attenuated by administration of WIN 55212-2. Furthermore, use of the selective antagonists for the CB1 receptor (SR 141716A) and the CB2 receptor (SR144528) in this study demonstrated that the cannabinoid's inhibitory effects on leukocyte/endothelial interactions can be mediated by activating CB2 receptor.

Animals↗

PubMed2003

L-NAME (N omega-nitro-L-arginine methyl ester), a nitric-oxide synthase inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a cannabinoid agonist, interact to evoke synergistic hypothermia.

Cannabinoids evoke profound hypothermia in rats by activating central CB(1) receptors. Nitric oxide (NO), a prominent second messenger in central and peripheral neurons, also plays a crucial role in thermoregulation, with previous studies suggesting pyretic and antipyretic functions. Dense nitric-oxide synthase (NOS) staining and CB(1) receptor immunoreactivity have been detected in regions of the hypothalamus that regulate body temperature, suggesting that intimate NO-cannabinoid associations may exist in the central nervous system. The present study investigated the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, on the hypothermic response to WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a selective cannabinoid agonist, in rats. WIN 55212-2 (1-5 mg/kg, i.m.) produced dose-dependent hypothermia that peaked 45 to 90 min post-injection. L-NAME (10-100 mg/kg, i.m.) by itself did not significantly alter body temperature. However, a nonhypothermic dose of L-NAME (50 mg/kg) potentiated the hypothermia caused by WIN 55212-2 (0.5-5 mg/kg). The augmentation was strongly synergistic, indicated by a 2.5-fold increase in the relative potency of WIN 55212-2. The inactive enantiomer of WIN 55212-2, WIN 55212-3 [S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate] (5 mg/kg, i.m.), did not produce hypothermia in the absence or presence of L-NAME (50 mg/kg), confirming that cannabinoid receptors mediated the synergy. The present data are the first evidence that drug combinations of NOS blockers and cannabinoid agonists produce synergistic hypothermia. Thus, NO and cannabinoid systems may interact to induce superadditive hypothermia.

Animals↗

PubMed2003

NMDA receptors modulate morphine-induced hyperthermia.

An accumulating body of evidence indicates that activation of NMDA receptor complexes modulates a number of morphine-induced responses. Because a single injection of morphine increases extracellular glutamate levels and downregulates NMDA receptors, acute morphine appears to increase glutamatergic transmission. On the basis of those data and the fact that morphine and glutamate induce hyperthermia, we investigated whether NMDA receptors modulate the hyperthermic effects of acute morphine in male Sprague-Dawley rats. Subcutaneous injection of morphine (0.1-15 mg/kg) evoked dose-dependent hyperthermia, which was rapid in onset and peaked 45-60 min post-injection. Pretreatment with LY 235959 (0.1-1 mg/kg, s.c.), a highly selective and competitive NMDA antagonist, or dextromethorphan (5-15 mg/kg, s.c.), a noncompetitive NMDA antagonist, attenuated the hyperthermic effect of morphine (4 mg/kg). In contrast, administration of LY 235959 (1 mg/kg) 15 min after morphine (4 mg/kg) did not reverse the hyperthermia. LY 235959 (1 mg/kg) depressed the hyperthermia caused by DAMGO (1 micro g/rat, i.c.v.), a selective mu agonist, confirming that NMDA receptor activation maximizes mu receptor-induced hyperthermia. Neither LY 2359595 nor dextromethorphan by itself significantly altered body temperature. These data indicate that NMDA receptors modulate morphine-induced hyperthermia and suggest that increases in glutamatergic transmission maximize the hyperthermia evoked by morphine.

Animals↗