Abstract
Introduction
Although opioids are widely prescribed for pain, in many circumstances, they have only modest efficacy. Preclinical studies have shown that chemokines, immune mediators released ...during tissue injury and inflammation, can desensitize opioid receptors and block opioid analgesia by a process termed “heterologous desensitization.” The present studies tested the hypothesis that in evoked pain, certain chemokine receptor antagonists (CRAs), given with a submaximal dose of morphine, would result in enhanced morphine potency.
Methods
Three rodent pain assays were used: incisional pain in rats, the cold-water tail flick test in rats, and the formalin test in mice. The FDA-approved, commercially available CRAs, maraviroc and AMD3100, were used. They block the chemokine receptors and ligands, CCR5/CCL5 (RANTES) and CXCR4/CXCL4 (SDF-1α), respectively.
Results
In the incisional pain assay, it was found that the combination of a single CRA, or of both CRAs, with morphine significantly shifted the morphine dose-response curve to the left, as much as 3.3-fold. In the cold-water tail flick and formalin tests, significant increases of the antinociceptive effects of morphine were also observed when combined with CRAs.
Conclusions
These results support the potential of a new “opioid-sparing” approach for pain treatment, which combines CRAs with reduced doses of morphine.
Acinetobacter baumannii
is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous ...animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to
Acinetobacter
infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several
Acinetobacter
strains. Morphine administered for 48 h by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone.
Acinetobacter
burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A
−/−
mice given morphine were not sensitized to
Acintobacter
infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates
Acinetobacter
infection.
Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever. The mechanisms involved in the pathogenesis of these ...syndromes are not well defined, and neither are the brain areas involved. The present study tests a new hypothesis: that the preoptic anterior hypothalamus (POAH), the main brain area for thermoregulation and fever, has a role in the pathogenesis of fever induced by glycoprotein 120 (gp120), the surface envelope protein used by the HIV to gain access into immune cells, and that the CXC chemokine receptors (CXCR4) that serve as a coreceptor for HIV entry mediate the effect. A sterilized stainless steel C313G cannula guide was implanted into the POAH, and a biotelemetry system was used to monitor the body temperature (Tb) changes. The administration of gp120 into the POAH induced fever in a dose-dependent manner. To demonstrate possible links between the gp120 and CXCR4 in generating the fever, we pretreated the rats with 1,1'-1,4-phenylenebis(methylene)bis1,4,8,11-tetraazacyclotetradecane octohydrobromide dihydrate (AMD 3100), an antagonist of stromal cell-derived growth factor (SDF)-1alpha/CXCL12, acting at its receptor, CXCR4, 30 min before administration of gp120. AMD 3100 significantly reduced the gp120-induced fever. The present studies show that the presence of HIV-1 envelope glycoprotein gp120 in the POAH provokes fever via interaction CXCR4 pathway.
In this study we investigated the capacity of morphine to modulate expression of cytokines in peritoneal macrophages. Mice were implanted subcutaneously with a 75-mg morphine slow-release pellet, and ...48 h later resident peritoneal macrophages were harvested. Control groups received placebo pellets, naltrexone pellets, or morphine plus naltrexone pellets. Adherent cells were stimulated with lipopolysaccharide (LPS: 10 microg/mL) plus interferon-gamma (IFN-gamma: 100 units/mL) to induce cytokine production. After 24 h RNA was extracted for analysis of cytokine mRNA levels by reverse transcriptase-polymerase chain reaction, or supernatants were collected after 48 h for determination of cytokine production by enzyme-linked immunosorbent assay (ELISA). Morphine enhanced mRNA expression of interleukin (IL)-12 p40 and tumor necrosis factor alpha (TNF-alpha) compared with controls, whereas IL-10 levels were unchanged by drug treatment. ELISA data showed that both IL-12 p40 and p70 were increased by morphine. The enhancement of IL-12 at both the mRNA and protein levels was antagonized by naltrexone, indicating that the modulation of this cytokine by morphine is via a classic opioid receptor. These results are particularly interesting in light of our previous observation that 48 h after morphine pellet implantation, the peritoneal cavity is colonized with gram-negative and other enteric bacteria. The enhancement of IL-12 by morphine might be related to morphine-induced sepsis.
Highlight ► These studies are the first to demonstrate that the analgesic activity of morphine can be reduced by the presence of gp120 in the PAG via CXCR4 receptor activation.
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.
Review of the robust literature using acute drug injection paradigms points clearly to the conclusion that morphine is immunosuppressive. In contrast, studies of the effect of subacute or chronic ...administration of morphine on immune function is limited, with variable results. In some cases tolerance to the immunosuppressive effects of the drug is clearly demonstrated, but in other cases, selected immune parameters do not demonstrate tolerance. Discrepancies in findings may result from differences in species or route and manner of drug administration. Even fewer studies (total of 10) have been published on the effects of withdrawal on immune function. Most immune parameters tested are suppressed following drug withdrawal. Recovery time to baseline response levels varies in the studies. In the single report of withdrawal in humans, immune function was suppressed for up to 3 years. It is clearly established that withdrawal suppresses capacity of murine spleen cells to make an ex vivo antibody response, which contrasts with evidence of polarization of the lymphocytes towards a Th2 phenotype. Several laboratories have shown that subacute and chronic exposure to morphine, as well as drug withdrawal, sensitize to the lethal effects of bacterial lipopolysaccharide. Underlying sepsis, combined with morphine-induced hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis, may be occult variables modulating immune responses during opioid administration and withdrawal. As episodes of withdrawal are common among drug abusers, more intensive investigation is warranted on the effects of withdrawal on immune function, on mechanisms of immune modulation, and on sensitization to infection.
Multiple sclerosis (MS) is the most common of the immune demyelinating disorders of the central nervous system (C NS). 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. C annabinoid receptor agonists have been shown to downregulate immune responses and there is preliminary evidence that they may slow the progress of MS. The purpo se of this investigation was to determine how cannabinoid recepto r agonists interfere with leukocyte rolling and adhesion. This was investigated in an experimental autoimmune encephalo myelitis (EAE) model using six to eight week old C 57BL/6 mice. Mouse myelin oligodendrocyte protein and pertussis toxin were used to induce EAE. WIN 55212-2, C B1 and C B2 antagonist were given. By use of in vivo intravital microscopy, leukocyte/endothelial interactio ns 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 interactio n can be attenuated by administration of WIN 55212-2. Furthermore, use of the selective antagonists for the C B1 recepto r (SR 141716A) and the C B2 receptor (SR144528) in this study demonstrated that the cannabinoid’s inhibitory effects on leukocyte/endothelial interactions can be mediated by activating C B2 receptor.
Background and purpose: The chemokine, stromal cell‐derived growth factor‐1α (SDF‐1α/CXCL12), a member of the CXC chemokine family, and the ligand for CXCR4, the co‐receptor involved in the entry of ...human immunodeficiency virus‐1 (HIV‐1), was tested for its possible interaction with a physiological response to a cannabinoid.
Experimental approach: The cannabinoid agonist, an aminoalkylindole, (+)‐WIN 55,212‐2 (4,5‐dihydro‐2‐methyl‐4(4‐morpholinylmethyl)‐1‐(1‐naphthalenyl‐carbonyl)‐6H‐pyrrolo3,2,1ijquinolin‐6‐one, was infused directly into the preoptic anterior hypothalamus (POAH), the primary brain area involved in thermoregulation.
Key results: WIN 55,212‐2 (5–15 µg) evoked a dose‐related hypothermia, which was attenuated by SDF‐1α/CXCL12 microinjected directly into the POAH. The inhibitory effect of SDF‐1α/CXCL12 on WIN 55,212‐2‐induced hypothermia was reversed by 1,1′‐1,4‐phenylenebis(methylene)bis1,4,8,11‐tetraazacyclotetradecane octohydrobromide dihydrate, an antagonist of SDF‐1α/CXCL12, acting at its receptor, CXCR4.
Conclusion and implications: This study provides the first in vivo evidence for a thermoregulatory interaction between the HIV‐1 co‐receptor and the cannabinoid system in the brain.
Attenuated
Salmonella induce immunosuppressive, microbicidal and tumoricidal macrophages in mice. All three effects are mediated by activated macrophages producing nitric oxide (NO). NO is induced by ...the innate immune response pathway involving IL-12, NK cells and IFN-γ in response to infection. NO has beneficial and detrimental effects on the host.
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