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Biomedical subjects

D J Carr

Publications and source records attributed to D J Carr.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cytokines and endotoxin removal by sorbents and its application in push-pull sorbent-based pheresis: the BioLogic-DTPF System.

The BioLogic-DTPF System (DTPF) combines the Biologic-DT hemodiabsorption system (DT) in series with the Biologic PF push-pull pheresis system (PF) in which PF membranes separate plasma for direct contact between plasma proteins and the sorbents. Preliminary studies conducted in bovine serum albumin (BSA) solution and in bovine plasma allowed charcoal and silica to be evaluated as adsorbents for the PF module. Equilibrium binding experiments in BSA showed a high capacity of cytokine (IL-1 beta, TNF alpha) binding by powdered charcoal, 70-90 ng/g. Kinetic binding studies in bovine plasma revealed relatively quick adsorption of IL-1 beta and IL-6 by charcoal with the capacity range of 1.2-2.0 ng/g for tested cytokines (IL-1 beta and TNF alpha). Further laboratory studies with plasma have shown that powdered silica has an even greater binding capacity, up to 13 ng/g for TNF alpha depending upon particle size, and more rapid binding for all tested cytokines than powdered charcoal. Cholestyramine is a more efficient sorbent for removal of endotoxin than either charcoal or silica. In vitro tests using whole blood have demonstrated that the DTPF, with powdered charcoal as the sorbent, clears cytokines (TNF alpha, IL-1 beta, and IL-6) at 12.6-23.4 ml/min, bilirubin at 17.8-34.7 ml/min, and creatinine at 53.6-82.6 ml/min. The removal of some cytokines during the first clinical trial is also discussed.

Adsorption↗
PubMed1999

Transgenic expression of interleukin-6 in the central nervous system confers protection against acute herpes simplex virus type-1 infection.

IL-6 is a pro-inflammatory cytokine that has previously been associated with herpes simplex virus type 1 reactivation. To further investigate this relationship during acute infection, ocular HSV-1 infection was studied in transgenic mice homozygous or heterozygous expression of IL-6 by astrocytes in the central nervous system. The virus load in both the eye and trigeminal ganglia was significantly reduced at day 6 but not day 3 post infection in the homozygous IL-6 transgenic mice compared to the wild type and heterozygous littermates. IL-6 protein and mRNA levels in the eye coincided with the level of transgene expression in mice acutely infected with virus (i.e., day 3 post infection). Likewise, IL-6 transcript levels in the TG mirrored the expression of the transgene in the mice throughout the course of the infection into latency. The HSV-1 alpha lytic phase gene ICP27 was rapidly down-regulated by day 6 post infection in the TG of homozygous IL-6 transgenic mice compared to the wild type and heterozygous littermates. The resistance to acute HSV-1 infection in the homozygous IL-6 transgenic mice correlated with a significant elevation in IFN-alpha/beta in the eye compared to the wild type or heterozygous IL-6 transgenic animals. Heterozygous and homozygous IL-6 transgenic mice latently infected with HSV-1 showed elevated anti-HSV-1 antibody titers compared to the latently infected wild type controls. Collectively, the results suggest dose-dependent IL-6 antagonism of acute HSV-1 infection in vivo.

Acute Disease↗
PubMed1999

Push-pull sorbent-based pheresis treatment in an experimental canine endotoxemia model: preliminary report.

The Biologic-DTPF System (DTPF), an extracorporeal blood treatment device with potential to treat sepsis, was tested in a preliminary study using a canine endotoxemia model. Six dogs were used and they formed four treatment groups, as control group (n=1) and three groups based on the type of sorbent present in the plasma filter (PF) system: sham treatment with no sorbent (n=1), charcoal as sorbent (n=2), and charcoal/silica as sorbent ("silica" group, n=2). Cardiodynamic data were recorded before treatment and every 30 minutes, and blood samples were collected to determine blood chemistry and to detect the levels of endotoxin and selected plasma cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). The dogs were given Escherichia coli endotoxin (2 mg/kg) as an intravenous drip (extended over a period of 30 minutes). Thirty minutes after the end of infusion all animals except the control were treated with the DTPF system for four hours. To determine the effect of treatment, data collected at one hour from the initiation of treatment until the end of treatment were compared between control and treated dogs. The endotoxin levels in the control dog were higher (P < 0.05) than other groups. The control dog had lower levels of TNF than other groups. The control dog had similar levels of IL-1 (P > 0.05) and higher levels (P < 0.05) at 4 hours into treatment compared to other groups. The control dog had similar levels of IL-6 as other groups (P > 0.05). In the control dog, the mean arterial pressure (MAP) fell and then remained low but stable at 1-4 hours. The charcoal group had lower MAP than the control dog at 1-4 hours (P < 0.05). The silica group had higher MAP levels similar to the control dog. After treatment, the control dog had higher (P < 0.05) values of hematocrit, hemoglobin, calcium, potassium, and albumin compared to the treated groups. As expected for a system removing plasma during sepsis, the DTPF System had some adverse effects on the physiologic status of the dogs, especially when loaded with charcoal sorbent only. The findings of the present study suggest that the filters are capable of eliminating endotoxin and there is some evidence of cytokine removal. Although the charcoal dogs did poorly, addition of silica to the sorbent offset any negative effects. Further work is underway to improve the efficiency of the system, primarily to enhance the capacity of the sorbents for cytokines. A more realistic canine sepsis model with mortality after several days (the Escherichia coli- infected intraperitoneal clot) will also be considered in future studies.

Analysis of Variance↗
PubMed1998

Astrocyte-targeted expression of IFN-alpha1 protects mice from acute ocular herpes simplex virus type 1 infection.

Type I IFNs (i.e., IFN-alpha and IFN-beta) play a key role in the host's innate defense against viral pathogens. To examine the biologic relevance of IFN-alpha to a viral pathogen within the confines of the nervous system, IFN-alpha1 transgenic mice whose transgene is under the control of the glial fibrillary acidic protein promoter (GFAP-IFN-alpha, astrocyte specific) were examined for resistance to an ocular herpes simplex virus type 1 (HSV-1) infection. GFAP-IFN-alpha mice expressed significantly higher levels of IFN-alphabeta (533 U) in the trigeminal ganglion compared with nontransgenic mice (70 U) 72 h postinfection that corresponded with a significant reduction in the mRNA expression of the HSV-1 immediate early gene infected cell polypeptide 27 and late gene VP16, as well as the chemokines monocyte-chemoattractant protein-1 and cytokine response gene-2 in the eye and trigeminal ganglion. Six days postinfection, the viral load and the expression of infected cell polypeptide 27, CD8, RANTES, IFN-gamma, and IFN-alpha mRNA levels were reduced in the trigeminal ganglion of GFAP-IFN-alpha mice compared with the wild-type mice. Following the establishment of HSV-1 latency (i.e., 30 days postinfection), only one of nine (11%) GFAP-IFN-alpha mice was found to be latent compared with seven of eight (88%) of the wild-type mice, as determined by the expression of the latency-associated transcript RNAs. Likewise, only three of nine GFAP-IFN-alpha mice screened showed seroconversion by day 30 postinfection compared with nine of ten wild-type mice screened. Collectively, the results show that the IFN-alpha1 transgenic mice are less susceptible to acute HSV-1 infection and the establishment of viral latency.

Animals↗
PubMed1998

Increased levels of IFN-gamma in the trigeminal ganglion correlate with protection against HSV-1-induced encephalitis following subcutaneous administration with androstenediol.

Androstenediol (AED) is a metabolic product of dehydroepiandrosterone (DHEA), an adrenal steroid known to possess immunomodulatory characteristics. The present study was undertaken to assess the efficacy of AED treatment in mice ocularly infected with herpes simplex virus type 1 (HSV-1). The subcutaneous administration of 320 mg/kg AED 4 h prior to viral inoculation was found to enhance the survival of HSV-1-infected mice while lower doses (32.0-100.0 mg/kg) were without effect. However, there were no apparent differences in the viral load in the eye or trigeminal ganglion (TG) 3 or 6 days post infection (p.i.) in vehicle- or AED (320 mg/kg)-treated mice. Likewise, there were no differences in the expression of cytokine or chemokine mRNAs in the eyes or TG early (i.e., 3 days p.i.) following infection. However, by 6 days p.i., there was a significant increase in the expression of the chemokines IP-10, MCP-1, and RANTES and the cytokines interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) in the AED (320 mg/kg)-treated mice compared to vehicle-treated controls as determined by reverse transcription (RT)-polymerase chain reaction (PCR) and quantitative PCR (for IFN-gamma). Likewise, there was a corresponding increase in IFN-gamma and IL-2 but not IL-12 protein in the TG of AED-treated mice 6 days p.i. AED-treatment also induced a rise in splenic natural killer activity in a dose- and time-dependent fashion. Collectively, these results suggest that the protective effect following subcutaneous administration of AED is associated in a rise in selective type 1 cytokines (IL-2 and IFN-gamma) as well as natural killer activity.

Anabolic Agents↗
PubMed1998

Role of the hypothalamic pituitary adrenal axis and IL-6 in stress-induced reactivation of latent herpes simplex virus type 1.

Hyperthermic stress induces reactivation of herpes simplex virus type 1 (HSV-1) in latently infected mice and also stimulates corticosterone release from the adrenals via activation of the hypothalamic pituitary adrenal axis. In the present study, we tested the hypothesis that stress-induced elevation of corticosterone potentiates HSV-1 reactivation in latently infected mice. Because of the putative role of IL-6 in facilitating HSV-1 reactivation in mice, the effect of hyperthermic stress and cyanoketone treatment on IL-6 expression in the trigeminal ganglion was also measured. Preadministration of cyanoketone, a glucocorticoid synthesis inhibitor, blocked the stress-induced elevation of corticosterone in a dose-dependent manner. Furthermore, inhibition of corticosterone synthesis was correlated with reduced levels of HSV-1 reactivation in latently infected mice. Hyperthermic stress elicited a transient rise in IL-6 mRNA levels in the trigeminal ganglion, but not other cytokine transcripts investigated. In addition, there was a significant reduction in MAC-3+, CD8+, and DX5+ (NK cell marker) cells in the trigeminal ganglion of latent HSV-1-infected mice 24 h after stress. Cyanoketone blocked the stress-induced rise in IL-6 mRNA and protein expression in the trigeminal ganglion latently infected with HSV-1. Collectively, the results indicate that the activation of the hypothalamic pituitary adrenal axis plays an important role in stimulating IL-6 expression and HSV-1 reactivation in the trigeminal ganglion following hyperthermic stress of mice.

Animals↗
PubMed1998

Cytokine and chemokine production in HSV-1 latently infected trigeminal ganglion cell cultures: effects of hyperthermic stress.

The establishment of a primary trigeminal ganglion (TG) cell culture latently infected with herpes simplex virus type 1 (HSV-1) has been useful in studying stress-induced reactivation of the latent virus. However, the immune profile of this culture system prior to and after stress has never been established. In the present manuscript, cytokine and chemokine production were measured in primary cultures of TG cells obtained from uninfected and HSV-1 latently infected mice. Supernates from TG cell cultures contained detectable interleukin (IL)-6 but not IL-1beta, IL-2, IL-10, interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha as determined by ELISA. The basal level of IL-6 in uninfected TG cell cultures was 20.5 +/- 2.3 ng/ml, whereas latently infected TG cells produced significantly less IL-6 (12.1 +/- 1.9 ng/ml). Supernates from TG cell cultures also contained detectable levels of C-10, MCP-1 and eotaxin but little to no MIP-1alpha, MIP-1beta, or MIP-2. While there were no differences in the basal level of MCP-1 and eotaxin in TG cell cultures from HSV-1-infected and uninfected mice, C10 levels were significantly higher in TG cultures originating from infected mice compared to uninfected ones (5.86 +/- 0.61 ng/ml compared to 1.18 +/- 0.16 ng/ml). Hyperthermic stress (43 degrees C, 180 min), which induces reactivation of latent HSV-1 from TG cell cultures, significantly reduced IL-6 and C-10 levels from both uninfected and latently infected TG cell cultures. However, there was no correlation between cytokine/chemokine levels and HSV-1 reactivation. Immunofluorescent studies showed TG cell cultures contained 10% MAC-3+ staining cells (macrophage specific) but no dendritic cells. By comparison, cells from freshly isolated TG contained 6% positive dendritic cells but < 1% MAC-3 + cells. Both in vivo and in vitro TG consisted of a low percentage of CD3+ and CD8+ cells. Hyperthermic stress (43 degrees C for 3 h) eliminated the lymphocyte population as determined by RT-PCR. Whereas no spontaneous reactivation has been reported in mice, spontaneous reactivation occurred in 4.5% (10/220) of TG cell cultures surveyed over a 20 day period. Collectively, the dichotomy between HSV-1 replication and reactivation comparing the in vitro and in vivo HSV-1 latency models may reside, in part, to the differences in the levels of cytokines, chemokines and immune cell populations within the microenvironment of the in vitro and in vivo TG.

Animals↗
PubMed1998

Androstenediol antagonizes herpes simplex virus type 1-induced encephalitis through the augmentation of type I IFN production.

Dehydroepiandrosterone and androstenediol (AED) have previously been found to protect mice from viral-induced encephalitis resulting in an increased survival rate of the animals. These hormones have been shown to antagonize corticosteroids, which have immunosuppressive effects in vivo and in vitro, suggesting the antiviral effect of DHEA and AED may be linked to the anticorticosteroid action. The present study was undertaken to address the immune response to herpes simplex virus type 1 (HSV-1) during the acute ocular infection with and without AED treatment focusing on the early immune events in the eye and trigeminal ganglion. AED treatment was found to significantly improve the survival of HSV-1-infected mice in a dose-dependent fashion. While AED did not antagonize the elevated serum corticosterone levels following acute infection, AED enhanced the expression of IFN-alpha mRNA and decreased the expression of HSV-1-infected cell polypeptide 27 mRNA in the trigeminal ganglion during the acute (day 6 postinfection) infection of mice, as determined by reverse transcription-PCR. However, there was no change in the viral load from the eye or trigeminal ganglion when comparing the AED-treated with the vehicle-treated mice. Neutralization Abs to IFN-alpha, -beta, or -alpha/beta, but not control Ab, blocked the protective effect following AED exposure, confirming the involvement of type I IFN in the enhancement of survival in AED-treated mice. Collectively, these results identify innate immunity as a key component in augmenting the survival of HSV-1-infected mice following AED treatment.

Androstenediol↗
PubMed1998

The persistent elevated cytokine mRNA levels in trigeminal ganglia of mice latently infected with HSV-1 are not due to the presence of latency associated transcript (LAT) RNAs.

Trigeminal ganglia (TG) from mice latently infected with wild type HSV-1 contain detectable levels of cytokine transcripts that are not present in TG from uninfected mice. This suggests that during HSV-1 neuronal latency, the immune system is stimulated by the production of one or more viral proteins. Since the LAT (latency associated transcript) gene is essential for wild type levels of spontaneous reactivation and is the only highly active viral gene during latency, the stimulation of cytokines may indicate the presence of a LAT encoded latency protein. We therefore compared the cytokine transcript profiles in the TG of mice latently infected with wild type and LAT negative viruses. Mice were latently infected with either: (1) the LAT null mutant dLAT2903; (2) its marker rescued virus dLAT2903R; or (3) the parental wild type HSV-1 strain McKrae. As expected, reactivation following explant cultivation of TG from latently infected mice was significantly decreased with dLAT2903 (P < 0.05)(40 +/- 8%, n = 24) compared with dLAT2903R (85 +/- 7.6%, n = 36) or the parental virus (70 +/- 10.0%, n = 36). The relative levels of various cytokines was determined by RT-PCR analysis of TG extracts. None of the cytokine transcripts detected in mice latently infected with the wild type or marker rescued viruses were missing or decreased in mice latently infected with the LAT null mutant 30 or 60 days post infection. There were also no differences in the HSV-1 antibody titers induced by the LAT negative virus compared to the LAT positive viruses. Thus, although LAT facilitated reactivation of HSV-1 from explanted mouse TG, expression of LAT during latency did not appear to be involved in persistent cytokine expression in TG. This suggests that during latency, HSV-1 does not produce a highly antigenic abundant LAT encoded protein.

Animals↗
PubMed1998

Immunization with HSV-1 antigen rapidly protects against HSV-1-induced encephalitis and is IFN-gamma independent.

Herpes simplex virus type 1 (HSV-1) infection of mice frequently culminates in fatal encephalitis. Intraperitoneal administration of heat-inactivated HSV-1 0-5 days before infection (active immunization) protected mice from encephalitis. In addition, active immunization 2-5 days before ocular infection with HSV-1 reduced the frequency of establishment of latent HSV-1 infection in the trigeminal ganglion (TG). However, intraperitoneal administration of heat-inactivated HSV-1 did not induce interferon (IFN) production in the peritoneum or serum, as determined by bioassay and ELISA. Intraperitoneal administration of heat-attenuated HSV-1 elicited IFN-gamma but not type I IFN production in the peritoneum. The production of IFN-gamma correlated with the infiltration of CD4 and CD8 cells in the peritoneum as determined by RT-PCR. In addition, there was a significant increase in interleukin (IL)-12 p40, IL-12p35, IL-6, IL-10, and IFN-gamma mRNA in peritoneal cells, as determined by RT-PCR following immunization with heat-attenuated HSV-1, which was not observed using heat-inactivated HSV-1. The results suggest that resistance to HSV-1 is induced rapidly following immunization with viral antigen but that protection against encephalitis is independent of the cytokines that are generated in the peritoneum.

Analysis of Variance↗
PubMed1997

Acyclovir blocks cytokine gene expression in trigeminal ganglia latently infected with herpes simplex virus type 1.

We have previously found that interleukin (IL)-2, IL-10, interferon (IFN)-gamma, RANTES, and tumor necrosis factor (TNF)-alpha mRNA transcription remain elevated in the trigeminal ganglia (TG) of herpes simplex virus type 1 (HSV-1) latently infected mice up to 120 days postinoculation (p.i.). To determine if this phenomenon was dependent on HSV-1 DNA replication after the establishment of latency (i.e., reactivation), cytokine gene expression was compared in TG of acyclovir-treated and untreated latently infected mice. Oral acyclovir treatment (begun 16 days p.i.) had no effect on serum levels of total anti-HSV-1 antibodies. However, there was a significant reduction in the titer of antibody specific for glycoprotein D and glycoprotein B but not glycoprotein H/L 120 days PI in the acyclovir-treated compared to vehicle-treated mice. These differences were not significant at earlier time points (i.e., days 34 and 60 p.i.). Consistent with these findings, acyclovir had no effect on cytokine gene expression in latently infected TG 35 and 60 days p.i. However, 120 days p.i., IFN-gamma and TNF-alpha mRNA were approaching baseline levels in TG of acyclovir-treated mice, but remained significantly elevated in untreated controls (i.e., IFN-gamma mRNA levels were sixfold higher in TG of untreated mice). Therefore, viral DNA replication appears to provide an antigenic stimulus for persistent cytokine gene expression in latently infected TG.

Acyclovir↗
PubMed1997

Innate and acquired immunity to herpes simplex virus type 1.

Immunization with heat-inactivated herpes simplex virus type 1 (HSV-1) 2-5 days before ocular infection reduced the frequency of establishment of latent HSV-1 infection in the trigeminal ganglion (TG); this induction of resistance coincided with reduced expression of IFN-gamma mRNA in the TG. Immunization with unrelated antigens was not protective. In part, this resistance to nervous system invasion correlated with the appearance of serum antibody to HSV-1. Immunization reduced viral replication in the eye and trigeminal ganglion, and prevented HSV-1 spread to the cerebellum. IFN-gamma was detected in immunized mice 4 days postocular infection as determined by plaque reduction using neutralizing Ab to IFN-alpha/beta and IFN-gamma. Injection of antibody (Ab) to IFN-alpha/beta and IFN-gamma administered at the time of immunization did not affect survival. Anti-IFN-gamma-treated mice had significantly reduced levels of IFN in their serum. Treatment with anti-IFN-alpha/beta Ab resulted in an elevation in viral replication as determined by the expression of latency associated transcripts in the TG of mice. Likewise, there was a significant increase in the CD8, IL-12 (p40), and TNF-alpha mRNA levels in the TG of the anti-IFN-alpha/beta-treated mice TG explant cultures demonstrated that viral load was significantly increased in the TG of anti-IFN-alpha/beta-treated mice relative to TG of control mice 7 days after infection. The results suggest that exposure to viral antigens 2-5 days before infection is an important determinant of the extent of HSV-1 spread to the nervous system. Moreover, the data suggest that both an antibody response and IFN-alpha/beta play a role in limiting the progress of infection from the peripheral tissues to the central nervous system.

Animals↗
PubMed1996

Persistent cytokine expression in trigeminal ganglion latently infected with herpes simplex virus type 1.

Following ocular infection, herpes simplex virus type 1 (HSV-1) establishes latency in trigeminal ganglion (TG) neurons. Using reverse transcription-PCR, cytokine gene expression was analyzed in the TGs of mice infected with HSV-1. IL-2, TNF-alpha, IFN-gamma, IL-10, and RANTES mRNAs were readily detected in TGs taken from mice 7 days postinoculation (PI). Likewise, IL-2, IL-6, IL-10, and IFN-gamma protein were detected by ELISA of TG homogenates. Between 5 and 45 days PI, IL-10, IFN-gamma, TNF-alpha, and RANTES mRNAs were detected in nearly 100% of latently infected TGs (latent infection was confirmed by reverse transcription-PCR detection of HSV-1 latency-associated transcripts). T cell-associated cytokine and chemokine mRNAs (IL-2, IL-10, IFN-gamma, and RANTES) were still detected in the majority of latently infected TG samples taken between 60 and 135 days PI. In contrast, these cytokine mRNA species were rarely detected in uninfected TGs. Measurement of serum Abs to HSV-1 at different times revealed that anti-HSV-1 Ab concentrations approached a plateau in mice by 30 days PI but remained at high levels 67 and 125 days PI. Although there was molecular evidence of an ongoing immune response to HSV-1 in latently infected TG, histologic analysis indicated that very few mononuclear cells remained in the ganglion 60 days PI. Collectively, the results suggest that residual lymphocytes encounter viral Ag during HSV-1 latency with sufficient frequency to remain activated. The paradox of a persistent immune response against a latent infection is discussed.

Animals↗
PubMed1996

Aberrant regulation of cytokines in HIV-1 TAT72-transgenic mice.

The trans-activator of transcription or TAT gene from HIV-1 encodes a protein that increases the processivity of transcription from the HIV-1 genome. TAT protein can also affect cellular processes in the absence of its ribonucleic HIV target sequence trans activation response element and may be responsible for some aspects of HIV pathogenesis apart from infectious virus or other viral gene products. We have previously shown that TAT72 decreases CTL activity in TAT72-transgenic mice, and we now demonstrate aberrant regulation of mitogen-elicited IL-2 at both transcriptional and translational levels. In contrast, alloantigen stimulation resulted in increased IL-6 and IL-10 production in the TAT72-transgenic mice. Con A-stimulated cultures of splenic lymphocytes from TAT72-transgenic mice do not undergo clonal proliferation of CD4+ cells as compared with CD8+ cells monitored over 72 h. These results suggest that TAT is sufficient to induce some pathology associated with AIDS and is a potent immunologic manipulator apart from its function as trans-activator.

Animals↗
PubMed1996

Mirfentanil antagonizes morphine-induced suppression of splenic NK activity in mice.

Mirfentanil [N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide] was studied for its antinociceptive and immunomodulatory effects in mice Mirfentanil (1.0-32.0 mg/kg) increased tail-flick latency to a thermal stimulus and this effect was antagonized (94 +/- 2%) by naltrexone (10.0 mg/kg). Unlike naltrexone, the delta opioid selective antagonist naltrindole (20.0 mg/kg) had no effect on mirfentanil-induced analgesia. In a dose-dependent fashion, the mu-selective antagonists beta-funaltrexamine (1.0-40.0 mg/kg) and naloxonazine (1.0-35.0 mg/kg) blocked mirfentanil (10.0 mg/kg)-induced analgesia up to 75% of the maximum analgesic effect. Norbinaltorphimine (10.0 mg/kg) partially blocked (35%) the maximum analgesic effect following mirfentanil (10.0 mg/kg) administration. Single doses of mirfentanil (0.1-32.0 mg/kg) had no effect on splenic NK activity. However, preadministration of mirfentanil (1.0-10.0 mg/kg) blocked morphine-induced suppression of splenic NK activity. Collectively, the results suggest that mirfentanil is a novel opioid that induces antinociception predominately through mu opioid receptors but, unlike morphine or fentanyl, does not suppress splenic NK activity.

Adjuvants, Immunologic↗