Enhancement of the contact hypersensitivity reaction by acute morphine administration at the elicitation phase.

The present study investigated the effects of morphine on the irritant contact sensitivity (ICS) and contact hypersensitivity (CHS) reaction. ICS was induced by croton oil application on the pinnae of naïve rats. Morphine injected prior to croton oil application did not affect the ICS response when assessed by measurements of pinnae thickness. CHS was induced by applying the antigen 2,4-dinitro-1-fluorobenzene (DNFB) to the pinnae of rats sensitized to DNFB. Rats received an injection of morphine prior to either initial antigen exposure (sensitization) or antigen reexposure (challenge). Morphine prior to challenge, but not sensitization, resulted in a pronounced enhancement of the CHS response as measured by pinna thickness. Quantitative PCR also showed increased IFN-gamma mRNA levels in the inflamed tissue of morphine-treated rats. Naltrexone blocked the morphine-induced enhancement of the CHS response. The differential effects of morphine suggest that opioids have a more pronounced effect on in vivo immune responses that involve immunological memory.

Acetylcholinesterase monoclonal antibody-induced sympathectomy: effects on immune status and acute morphine-induced immunomodulation.

The present study examined the role of the sympathetic nervous system (SNS) in immunomodulation by using the acetylcholinesterase monoclonal antibody (AChE mAb)-induced sympathectomy model. As part of this investigation, the effects of AChE mAb treatment on the immune alterations produced by acute morphine treatment also were explored. Experimental rats received tail vein injections of murine monoclonal IgG2b antibodies against rat brain acetylcholinesterase, which produce a destruction of cholinergic, sympathetic preganglionic neurons and a resultant decrease in sympathetic activity. Control rats received tail vein injections of murine IgG antibodies, which do not affect sympathetic preganglionic neurons or sympathetic activity. One week after antibody treatment, rats received a subcutaneous injection of 15 mg/kg morphine or the saline vehicle. One hour after the morphine or saline injections, rats were sacrificed and immune assays were conducted. AChE mAb treatment increased the mitogen-stimulated proliferation of splenic T cells and interleukin-2 (IL-2) production by stimulated splenocytes, indicating that these immune measures are sensitive to the AChE mAb-induced alteration in sympathetic function. Treatment with AChE mAb did not alter the mitogen-stimulated proliferation of splenic B cells or blood T cells, splenic natural killer (NK) cell activity, or the production of interferon-gamma (IFN-gamma) by stimulated splenocytes, indicating that these immune measures are relatively insensitive to the AChE mAb-induced alteration in sympathetic activity. The AChE mAb-induced alteration in sympathetic activity did not affect the suppressive effects of acute morphine treatment on the mitogen-stimulated proliferative response of splenic T and B cells and blood T cells, splenic NK cell activity, and the production of IFN-gamma and IL-2 by stimulated splenocytes.

Genetic differences in social behavior: relation to natural killer cell function and susceptibility to tumor development.

The hypothesis that certain heritable personality traits would correlate with increased vulnerability to tumor development and reduced natural killer (NK) cell function was tested in mice selectively bred for high and low levels of aggression. This selection program produces a line of mice that fail to exhibit species typical, isolation-induced aggression, but appear socially inhibited in response to a novel partner mouse. All socially inhibited mice developed 3-methylcholanthrene-induced tumors compared with only 44% of the aggressive mice. Basal NK activity was also significantly lower among socially inhibited mice. Conversely, there were no line differences in NK activity between the aggressive line and nonselected, socially isolated mice, consistent with other unidirectional outcomes of this selective breeding program. No significant line differences were present for nonsocial measures of emotional reactivity (e.g., fearfulness) or serum corticosterone levels. These findings support the hypothesis that social "traits" may be related to immune function and tumor susceptibility.

Modulation of immune status by a conditioned aversive stimulus: evidence for the involvement of endogenous opioids.

Recent research has shown that presentations of an unconditioned aversive stimulus, such as electric shock, can induce alterations of immune function in rats. Furthermore, it has been demonstrated that an innocuous stimulus paired with an unconditioned aversive stimulus can acquire immunomodulatory properties. Research has suggested that endogenous opioid activity is responsible for the alterations of immune function by unconditioned aversive stimulation. The present study evaluated the effect of administration of opiate receptor antagonists, naltrexone and N-methylnaltrexone, on the immunomodulatory effect of a conditioned stimulus (CS) that had been paired with electric footshock. Naltrexone dose-dependently attenuated the CS-induced suppression of the in vitro proliferative response of splenic lymphocytes to concanavalin A, lipopolysaccharide, and a combination of ionomycin and phorbol myristate acetate. Naltrexone also attenuated the CS-induced reduction in natural-killer cell activity. In contrast, the quaternary form of naltrexone, N-methylnaltrexone, did not significantly attenuate the CS-induced immunomodulatory effects. Collectively, these findings indicate that endogenous opioid activity is involved in CS-induced alterations of immune function. Moreover, the lack of effectiveness of N-methylnaltrexone in attenuating the CS-induced immunomodulatory effect suggests that the opioid receptors involved in the effect are located in the central nervous system.

Suppression of the development of adjuvant arthritis by a conditioned aversive stimulus.

The present study evaluated the effect of a conditioned aversive stimulus (CS) on the development of adjuvant-induced arthritis in Lewis rats. Experiment 1 showed that presentation of a CS, on days 12, 14, and 16 following injection with adjuvant containing mycobacterium tuberculosis, resulted in a pronounced suppression of the development of arthritis as measured by a clinical disease severity rating scale and spleen weight. In contrast, presentation of the CS on days 0, 2, and 4 following injection did not have any effect on the development of arthritis. Experiment 2 showed that the suppression of adjuvant arthritis by exposure to the CS was blocked by administration of propranolol, a nonselective beta-adrenergic receptor antagonist. These results demonstrate that a CS can alter the development of adjuvant-induced arthritis, but the effect is dependent upon the timing of the antigen exposure and the presentation of the CS. Moreover, the present findings suggest that blocking beta-adrenergic receptors during presentations of the CS prevents the suppressive effect of the CS.