Biomedical subjects

Martin W Adler

Publications and source records attributed to Martin W Adler.

27 records · Page 2Linked to original sources

PubMed2003

Role of the nitric-oxide synthase isoforms during morphine-induced hyperthermia in rats.

Recently, we demonstrated that the diffusible messenger molecule nitric oxide (NO) is involved in the hyperthermic response induced by morphine by using a nonselective nitric-oxide synthase inhibitor, N-nitro-L-arginine methyl ester. The present work extended these studies to include 7-nitroindazole (7-NI), an inhibitor specific for neuronal nitric-oxide synthase (nNOS), N(5)-(-iminoethyl)-L-ornithine (L-NIO), an inhibitor of endothelial NOS (eNOS), and aminoguanidine (AG), a potent inhibitor of inducible NOS (iNOS). A biotelemetry system was used in this study to measure the body temperature (Tb). A dose of 7-NI (5 or 10 mg/kg), which did not affect Tb by itself, blocked the hyperthermia induced by morphine in a dose-dependent manner (15 mg/kg i.p.). However, pretreatment with L-NIO (10-20 mg/kg) or with AG (50 mg/kg) failed to alter the hyperthermia induced by morphine. L-NIO (10-20 mg/kg) or AG (50 mg/kg) had no effect on Tb. These results suggest the involvement of nNOS in morphine-induced hyperthermia.

Animals↗

PubMed2003

Withdrawal from morphine in mice suppresses splenic macrophage function, cytokine production, and costimulatory molecules.

We have previously shown that abstinence from morphine by either abrupt (AW) or precipitated (PW) withdrawal induces greater than 80% suppression in the capacity to mount an in vitro plaque-forming cell (PFC) response to sheep red blood cells at 24-h post withdrawal. Present studies on the mechanisms of immunosuppression showed that addition of normal unfractionated spleen cells, macrophage-enriched adherent cells, or CD11b(+) purified macrophages, to spleen cells taken from withdrawn mice, restored immune responses. Spleen cells from mice undergoing withdrawal also had decreased splenic mRNA and/or protein levels of IL-1beta, IL-1Ra, TNF-alpha, IL-12, and IFN-gamma. Addition of IL-1beta or IFN-gamma to AW cultures was able to reverse their immunosuppression. These results strongly suggest that morphine withdrawal results in a deficit of macrophage function.

Animals↗

PubMed2002

Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain.

The chemokines use G protein-coupled receptors to regulate the migratory and proadhesive responses of leukocytes. Based on observations that G protein-coupled receptors undergo heterologous desensitization, we have examined the ability of chemokines to also influence the perception of pain by cross-desensitizing opioid G protein-coupled receptors function in vitro and in vivo. We find that the chemotactic activities of both mu- and delta-opioid receptors are desensitized following activation of the chemokine receptors CCR5, CCR2, CCR7, and CXCR4 but not of the CXCR1 or CXCR2 receptors. Furthermore, we also find that pretreatment with RANTES/CCL5, the ligand for CCR1, and CCR5 or SDF-1alpha/CXCL12, the ligand for CXCR4, followed by opioid administration into the periaqueductal gray matter of the brain results in an increased rat tail flick response to a painful stimulus. Because chemokine administration into the periaqueductal gray matter inhibits opioid-induced analgesia, we propose that the activation of proinflammatory chemokine receptors down-regulates the analgesic functions of opioid receptors, and this enhances the perception of pain at inflammatory sites.

Analgesics, Opioid↗

PubMed2002

Effect of a mu-opioid receptor-selective antagonist on interleukin-6 fever.

The endogenous opioid system has been found to be involved in fever caused by pyrogens. Recent work in our laboratory has demonstrated that the mu-opioid receptor is involved in interleukin-1beta (IL-1beta)- and in lipopolysaccharide (LPS)-induced fevers. In the present study, we have investigated the role of the mu-opioid receptor in the preoptic anterior hypothalamus (POAH) in fever induced by interleukin-6 (IL-6). Following stereotaxic implantation of a guide cannula into the POAH for microinjection, radio transmitters to monitor body temperature (Tb) continuously were inserted intraperitoneally. Adult male Sprague-Dawley rats were microinjected with 0.5 microg of the selective mu-opioid receptor antagonist, cyclic D-phe-Cys-Try-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), into the POAH. Thirty min later, IL-6 (100 ng) was injected into the POAH. CTAP significantly blocked the IL-6 fever. CTAP alone had no effect on Tb during the 390-min recording period. These data indicate that mu-opioid receptors within the POAH mediate IL-6 fever and add to the increasing evidence that the opioid system is involved in the pathogenesis of fever in rats.

Animals↗

PubMed2002

Sigma sites mediate DTG-evoked hypothermia in rats.

1,3,-Di-o-tolylguanidine (DTG), a sigma agonist, produces hypothermia in rats, but the inability of purported sigma antagonists to block the hypothermia suggests that sites other than sigma may mediate the effect. Recently, N-[2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD 1047) has been identified as a functional sigma antagonist in vivo because of its high selectivity for sigma sites and its ability to block DTG-induced dystonia and cocaine-evoked behaviors. Therefore, the present study investigated the effect of BD 1047 on DTG-evoked hypothermia. DTG (1, 10, 20 and 30 mg/kg sc) induced dose-dependent hypothermia. The onset of DTG-induced hypothermia was rapid, with a reduction in body temperature observed 15 min postinjection. To determine whether sigma sites mediated DTG-induced hypothermia, BD 1047 was injected 30 min prior to DTG. BD 1047 (1, 5, 7.5 and 10 mg/kg sc) attenuated the hypothermia in a dose-dependent fashion, thus revealing a sigma site mechanism. The injection of BD 1047 alone did not alter body temperature, suggesting that endogenous sigma systems do not play a tonic role in thermoregulation. The present experiments demonstrate for the first time that a selective sigma antagonist attenuates sigma agonist-induced hypothermia. Moreover, these data provide further evidence that BD 1047 is an effective antagonist for characterizing sigma-mediated effects in vivo.

Animals↗

PubMed2002

Abrupt or precipitated withdrawal from morphine induces immunosuppression.

The present studies tested the effect of withdrawal from morphine by two different paradigms, abrupt withdrawal (AW) or precipitated withdrawal (PW), on the capacity of murine spleen cells to mount an in vitro antibody response. Mice were made dependent by chronic treatment using s.c. implanted morphine slow-release pellets. Splenocytes were harvested at various time points after withdrawal and the number of antibody-forming cells determined using a plaque-forming cell (PFC) assay. The results indicate that induction of abstinence from morphine in dependent mice by either paradigm caused marked immunosuppression between 24 and 48 h post-withdrawal. However, the kinetics of onset and recovery from immunosuppression were different in AW and PW.

Analgesics, Opioid↗

PubMed2002

Role of the nitric oxide pathway in kappa-opioid-induced hypothermia in rats.

The effect of central and peripheral administration of a nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), on the hypothermia induced by the selective kappa-opioid receptor agonist trans-(+/-)3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide methane sulfate (U50,488H) was studied in male Sprague-Dawley rats. In the first series of experiments, we examined the effect of subcutaneous (s.c.) administration of L-NAME on the hypothermia induced by s.c. injection of U50,488H. L-NAME, at a dose of 50 mg/kg s.c., had no influence on body temperature (Tb). Coadministration of L-NAME (50 mg/kg, s.c.) with U50,488H (10 mg/kg, s.c.) blocked the hypothermia induced by U50,488H. In the second series of experiments, we investigated the effect of intracerebroventricular (i.c.v.) administration of L-NAME on the hypothermia induced by s.c. injection of U50,488H. L-NAME itself, given i.c.v. at a dose of 1 mg/rat, did not evoke any change in Tb. Administration of L-NAME (1 mg/rat, i.c.v.) caused a significant suppression of U50,488H hypothermia. The results indicate that either central or peripheral nitric oxide synthesis is required for the production of hypothermia induced by U50,488H.

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

PubMed2002

N-methyl-D-aspartate antagonists and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one], a cannabinoid agonist, interact to produce synergistic hypothermia.

CB(1) cannabinoid receptors mediate profound hypothermia when cannabinoid agonists are administered to rats. Glutamate, the principal excitatory neurotransmitter in the central nervous system (CNS), is thought to tonically increase body temperature by activating N-methyl-D-aspartate (NMDA) receptors. Because NMDA antagonists block cannabinoid-induced antinociception and catalepsy, intimate glutamatergic-cannabinoid interactions may exist in the CNS. The present study investigated the effect of two NMDA antagonists on the hypothermic response to WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one], a selective cannabinoid agonist, in rats. WIN 55212-2 (1-10 mg/kg i.m.) produced dose-dependent hypothermia that peaked 60 to 180 min postinjection. Dextromethorphan (5-75 mg/kg i.m.), a noncompetitive NMDA antagonist, or LY 235959 [(-)-6-[phosphonomethyl-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-2-carboxylate]](1-4 mg/kg i.m.), a competitive and highly selective NMDA antagonist, evoked hypothermia in a dose-sensitive manner, suggesting that endogenous glutamate exerts a hyperthermic tone on body temperature. A dose of dextromethorphan (10 mg/kg) that did not affect body temperature by itself potentiated the hypothermic response to WIN 55212-2 (1, 2.5, or 5 mg/kg). The enhancement was strongly synergistic, indicated by a 2.7-fold increase in the relative potency of WIN 55212-2. Similarly, a dose of LY 235959 (1 mg/kg) that did not affect body temperature augmented the hypothermia associated with a single dose of WIN 55212-2 (2.5 mg/kg), thus confirming that NMDA receptors mediated the synergy. We have demonstrated previously that CB(1) receptors mediate WIN 55212-2-evoked hypothermia in rats. The present data are the first evidence that NMDA antagonists exert a potentiating effect on cannabinoid-induced hypothermia. Taken together, these data suggest that interactions between NMDA and CB(1) receptors produce synergistic hypothermia.

Animals↗

PubMed2002

CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia.

The present study investigated the effect of the selective cannabinoid agonist, WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on body temperature. WIN 55212-2 (1, 2.5, 5, and 10 mg/kg, i.m.) induced hypothermia in a dose-dependent manner. The peak hypothermia occurred 60 to 180 min postinjection. Body temperature was still suppressed 5 h after the injection of the highest dose of WIN 55212-2. The selective CB(1) antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] (5 and 10 mg/kg, i.m.), blocked the WIN 55212-2-induced hypothermia, suggesting that CB(1) receptor activation mediated the hypothermia. In contrast, the selective CB(2) antagonist, SR144528 [N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide)] (5 mg/kg, i.m.), did not alter the WIN 55212-2-induced hypothermia. Neither SR141716A nor SR144528 alone altered body temperature. WIN 55212-2 (1-30 microg/microl) injected directly into the preoptic anterior hypothalamic nucleus (POAH) induced hypothermia in an immediate and dose-dependent fashion. The hypothermia produced by intra-POAH injection of WIN 55212-2 was brief, with body temperature returning to baseline 60 min postinjection. SR141716A (5 mg/kg, i.m.) abolished the hypothermia induced by intra-POAH injection of WIN 55212-2 (30 microg/microl), indicating that CB(1) receptors in the POAH mediated the hypothermia. The present results confirm the idea that CB(1) receptors mediate the hypothermic response to cannabinoid agonists. Moreover, the present data suggest that 1) the POAH is the central locus for thermoregulation, and 2) CB(1) receptors within the POAH are the primary mediators of cannabinoid-induced hypothermia.

Analgesics↗