Morphine's immunologic and analgesic effects. Comparison of time course.
Explore the source record for details and available documents.
Analgesics, Opioid↗
Biomedical subjects
D T Lysle
Publications and source records attributed to D T Lysle.
Tolerance development to morphine-induced alterations of immune status.
A variety of in vitro immune measures were examined in groups of Lewis rats that chronically consumed either tap water or a 0.2, 0.4, or 0.6 mg/ml morphine drinking solution. Rats received a subcutaneous injection of either saline or 15 mg/kg morphine sulfate 1 h before sacrifice. In the drinking groups, the acute morphine injection significantly suppressed splenic natural killer (NK) cell activity, mitogen-stimulated splenic T- and B-cell proliferation and gamma-interferon (gamma-IFN) production. A single, acute injection of morphine did not suppress NK cell activity in rats that drank the two highest concentrations of morphine, whereas it did suppress the mitogen-stimulated splenic T- and B-cell proliferation and gamma-IFN production. These results suggest that rats that drank morphine for 20 days developed tolerance to morphine's suppressive effect on NK cell activity but not to other measures of immune status. Morphine drinking rats also developed tolerance to morphine's antinociceptive effects and revealed signs of physical dependence when the morphine solution was withdrawn or when naltrexone was administered.
Animals↗
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.
Acetylcholinesterase↗
Conditioned immunomodulation: investigations of the role of endogenous activity at mu, kappa, and delta opioid receptor subtypes.
The present investigations were designed to determine the role of activity at mu, kappa, and delta opioid receptor subtypes in conditioned immunomodulation by evaluating the effects of selective opioid receptor antagonists on conditioned stimulus-induced alterations in immune status. Lewis rats were exposed to an aversive conditioned stimulus that was developed through pairings with electric footshock. This aversive conditioned stimulus induces a reduction in splenic natural killer cell activity, splenocyte proliferation in response to mitogens, and diminished levels of interferon-gamma (IFN-gamma) production by splenocytes. Intracerebroventricular (i.c.v.) administration of the opioid antagonist naltrexone or the mu 1-selective antagonist naloxonazine blocked conditioned alterations of immune status, indicating that activity at mu-opioid receptors is involved in conditioned immunomodulation. Further support for the involvement of mu-opioid receptors within the central nervous system is provided by data showing that peripheral administration of naloxonazine, at doses shown to be effective when administered i.c.v., had no effect on conditioned alterations of immune status. Ventricular administration of the kappa receptor antagonist nor-binaltorphimine (nor-BNI) did not antagonize the immunomodulatory effects of the conditioned stimulus. Administration of the delta receptor antagonist naltrindole also did not antagonize the conditioned alterations of immune status. Collectively, the results of this study indicate that the alterations of immune status produced by an aversive conditioned stimulus require activity at mu-opioid receptors, possibly mu 1, within the central nervous system.
Animals↗
Comparison of the time course of morphine's analgesic and immunologic effects.
UNLABELLED: Morphine, an opioid analgesic commonly prescribed and abused, produces immune-altering effects. Whether morphine's antinociceptive and immunologic effects occur concurrently is unknown. Therefore, we investigated the time course of morphine's immunologic and antinociceptive effects. Rats were given a 15-mg/kg morphine injection (subcutaneously), and experimental assessments were taken at 30 min, 1 h, 2 h, 6 h, 12 h, and 24 h after treatment. Immune measures included natural killer (NK) cell activity, proliferation of splenic T and B lymphocytes, and cytokine production. Antinociception was assessed by using the tail withdrawal assay. Results show that morphine's immunomodulatory effects on NK cell activity begin within 30 min, continue for at least 12 h, and return to control values by 24 h. In contrast, proliferation of splenic T and B cells and interferon-gamma production are not altered within 30 min; maximal suppression occurs at 1 h, and recovery begins within 2 h. In all immune measures, therefore, maximal suppression is present at the 1-h time point, and recovery is complete within 24 h. Morphine induces antinociception 30 min to 2 h after drug administration; recovery is complete within 6 h. These results suggest the possibility that different mechanisms modulate morphine's immunologic and analgesic effects. IMPLICATIONS: Acute morphine treatment in rats produces immune alterations and antinociception. Although there are slight differences in morphine's maximal immunological and antinociceptive effects, morphine suppresses immune status at time points concordant with its antinociceptive effects. These effects should be considered when administering morphine to patients whose systems are immunocompromised.
Analgesia↗
Effects of centrally administered opioid agonists on macrophage nitric oxide production and splenic lymphocyte proliferation.
Explore the source record for details and available documents.
Analgesics↗
Evidence for sympathetic and adrenal involvement in the immunomodulatory effects of acute morphine treatment in rats.
The present study examined the involvement of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in the immunomodulatory effects of acute morphine treatment in rats. Chlorisondamine, a ganglionic blocker, was used to assess the involvement of sympathetic and sympathoadrenal activity. Adrenalectomized rats were used to assess the involvement of the adrenal cortex, which is regulated primarily by hypothalamic-pituitary-adrenal axis activity, and the adrenal medulla, which is regulated primarily by sympathetic activity. The results showed that both chlorisondamine and adrenalectomy antagonize morphine's suppressive effects on the proliferative response of splenic lymphocytes to concanavalin A (Con A), lipopolysaccharide or ionomycin/phorbol myristate acetate. Chlorisondamine, but not adrenalectomy, antagonizes morphine's suppressive effects on phytohemagglutinin (PHA)-stimulated proliferation of splenic lymphocytes and interferon-gamma production by stimulated splenocytes. Adrenalectomy, but not chlorisondamine, blocks morphine's suppressive effects on the proliferative response of blood lymphocytes to Con A or PHA. Neither chlorisondamine nor adrenalectomy alters morphine's suppressive effect on splenic natural killer cell cytotoxicity. Collectively, these results suggest that sympathoadrenal activity is involved in the suppressive effects of acute morphine treatment on the proliferative response of splenic T and B cells to Con A, lipopolysaccharide or ionomycin/phorbol myristate acetate. Morphine's suppressive effects on the proliferative response of splenic T cells to PHA and the production of interferon-gamma by stimulated splenocytes also involve sympathetic activity, but not sympathoadrenal activity. The results suggest further that morphine's suppressive effects on the proliferative response of blood T cells to Con A or PHA do not involve sympathetic activity, but rather adrenocortical activity. Neither sympathetic nor adrenocortical activity appears to be involved in morphine's suppressive effect on splenic natural killer cell cytotoxicity.
Adrenalectomy↗
Assessment of the involvement of central nervous system and peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rats.
The present study assessed the involvement of opioid receptors both in the central nervous system (CNS) and in the periphery (i.e., on immunocytes) in the immune alterations produced by acute morphine treatment in rats. The first experiment showed that the in vitro suppressive effects of morphine on the mitogen-stimulated proliferation of splenic and blood lymphocytes are produced only by a very high concentration of morphine and are not naltrexone-reversible. These results suggest that the in vitro immunomodulatory effects of morphine are not mediated by classical opioid receptors on immunocytes. A second experiment showed that s.c. doses of N-methylnaltrexone that do not gain access to the CNS, as determined by the tail-withdrawal assay, do not antagonize the suppressive effects of a single, s.c. injection of morphine on the mitogen-stimulated proliferation of splenic and blood lymphocytes, splenic natural killer cell activity and the production of interferon-gamma by stimulated splenocytes. Only a high s.c. dose of N-methylnaltrexone that does gain access to the CNS, as determined by the tail-withdrawal assay, blocks morphine's immunomodulatory effects. A third experiment demonstrated that N-methylnaltrexone is 4 to 5 log units more potent in antagonizing most of the immune alterations produced by a single, s.c. injection of morphine when administered i.c.v. than s.c. Taken together, the results of the present study strongly suggest that CNS opioid receptors play an important role in the immune alterations produced by acute morphine treatment in rats.
Analgesics, Opioid↗
Evidence for the involvement of the caudal region of the periaqueductal gray in a subset of morphine-induced alterations of immune status.
This study was directed at determining whether morphine's immunomodulatory effects are mediated through the periaqueductal gray (PAG). The initial study showed that microinjection of morphine (0.0, 0.4, 4.0, or 40.0 micrograms/rat) into the lateral ventricle induces pronounced dose-dependent reductions in lymphocyte proliferation to T- and B-cell mitogens, natural killer cell cytotoxicity, and the production of interleukin-2 and interferon-gamma. In contrast, microinjection of morphine (0.0, 0.004, 0.04, 0.4, or 4.0 micrograms/rat) into the caudal aspect of the PAG induced dose-dependent alterations in natural killer cell cytotoxicity, but had no effect on lymphocyte proliferation or cytokine production. These results indicate that opioid receptors in the PAG are involved in the regulation of natural killer cell activity, but are not associated with morphine's effects on proliferation or cytokine production. A subsequent study showed that the effect of morphine in the PAG is restricted to the more caudal aspects of the PAG because microinjections of morphine into the rostral aspects do not result in any alteration of immune status. To determine that the activation of opioid receptors in the PAG is not only sufficient, but is required for morphine's effects on natural killer cell activity, N-methylnaltrexone was administered into the PAG (0, 0.0001, 0.001, or 0.01 micrograms/rat) before the systemic administration of morphine (15 mg/kg), a dose that induces pronounced alterations of natural killer cell activity. The results showed that the administration of N-methylnaltrexone directly into the PAG antagonized morphine's effects on natural killer cell activity, which indicate that activation of opioid receptors within the PAG are required for morphine to alter natural killer cell activity. Collectively, this study showed that activation of opioid receptors within the more caudal aspects of the PAG are required for morphine to induce alterations in splenic natural killer cell activity. The results also suggest that other brain regions are responsible for morphine's effect on lymphocyte proliferation and cytokine production.
Adjuvants, Immunologic↗
Evidence for the involvement of macrophage-derived nitric oxide in the immunomodulatory effect of morphine and aversive Pavlovian conditioning.
Explore the source record for details and available documents.
Adjuvants, Immunologic↗
Mechanisms whereby macrophage-derived nitric oxide is involved in morphine-induced immunomodulation.
Explore the source record for details and available documents.
Adjuvants, Immunologic↗
Effects of central administration of morphine on immune status in Lewis and Wistar rats.
Explore the source record for details and available documents.
Animals↗
Corticotropin-releasing hormone is involved in conditioned stimulus-induced reduction of natural killer cell activity but not in conditioned alterations in cytokine production or proliferation responses.
Research from our laboratory has demonstrated that the presentation of an aversive conditioned stimulus produces pronounced suppression of several in vitro measures of immune status. The present study was designed to evaluate the role of central corticotropin-releasing hormone (CRH) in the mechanisms mediating these conditioned effects. The aversive conditioned stimulus was a distinct environment that had previously been associated with electric footshock. Lewis rats received intraventricular administration of either buffered saline or a dose of the CRH-selective receptor antagonist alpha-helical CRH(9-41) (0, 0.5, 5, or 50 micrograms) prior to exposure to the aversive conditioned stimulus or home cage control treatment. The aversive conditioned stimulus produced decreases in splenic natural killer cell activity, splenocyte responsiveness to the mitogens concanavalin A (ConA), phytohemagglutinin (PHA), lipopolysaccharide (LPS), and the combination of ionomycin and phorbol myristate acetate (PMA), blood leukocyte responsiveness to ConA and PHA, and the production of interleukin-2 and interferon-gamma by activated splenocytes. The conditioned stimulus also produced an increase in plasma levels of corticosterone. Pretreatment with alpha-helical CRH(9-14) completely blocked the conditioned stimulus-induced suppression of natural killer cell activity. The CRH antagonist had no attenuative effect on the conditioned suppression of splenocyte or blood leukocyte proliferation in response to mitogens, or the production of interleukin-2 or interferon-gamma by activated splenocytes. There was also no effect of alpha-helical CRH(9-14) on the conditioned stimulus-induced increase in plasma corticosterone. These findings suggest that conditioned stimulus-induced suppression of natural killer cell activity is mediated by a mechanism that involves activity at central CRH receptors, and that this conditioned modulation is independent of HPA activation. Furthermore, these results indicate that the mechanisms involved in conditioned stimulus-induced suppression of proliferative or cytokine production responses are distinct from those involved in the modulation of natural killer cell activity.
Animals↗
Mechanisms of conditioned immunomodulation.
This article presents some recent work from our laboratory indicating that multiple physiological systems play a role in conditioned immunomodulation. The first study shows that naltrexone, but not N-methylnaltrexone, blocks the suppressive effects of an aversive conditioned stimulus on Con-A-induced proliferation and natural killer cell activity of splenic lymphocytes. This finding indicates that central opioid activity is involved in the conditioned effects. The second study shows that the beta-adrenergic antagonists atenolol and ICI-118,551 block of the suppressive effects of an aversive conditioned stimulus on Con-A-induced proliferation, but have no effect on natural killer cell activity. This result indicates the involvement of the adrenergic system in a subset of the conditioned effects. Collectively, these experiments provide evidence that both the opioid system and the sympathetic nervous system are involved in conditioned immunomodulatory changes elicited by an aversive conditioned stimulus.
Animals↗
Mechanisms whereby macrophage-derived nitric oxide is involved in morphine-induced suppression of splenic lymphocyte proliferation.
Previous research by our laboratory demonstrated that in vivo administration of morphine to rats suppresses concanavalin-A (Con-A)-stimulated proliferation of splenic lymphocytes in a dose-dependent, naltrexone-reversible manner. More recently, we showed that morphine-induced suppression of Con A-stimulated proliferation of lymphocytes depends on an increase in macrophage production of nitric oxide (NO) in splenocyte cultures. The present study investigated effector mechanisms through which morphine-induced increases in macrophage-derived NO decrease lymphocyte proliferation in Con A-stimulated splenocyte cultures. The results show that the addition of hemoglobin, a scavenger of extracellular NO, to Con A-stimulated splenocyte cultures dose-dependently attenuates the suppressive effect of morphine on proliferation. The addition of superoxide dismutase, a scavenger of superoxide anions, to splenocyte cultures does not antagonize the suppressive effect of morphine on Con A-stimulated proliferation. The addition of either methylene blue or 6-anilino-5, 8-quinolinedione (LY 83583), two inhibitors of soluble guanylate cyclase, to splenocyte cultures dose-dependently antagonizes the suppressive effect of morphine on Con A-stimulated proliferation. Taken together with our previous results, the present results suggest that in vivo administration of morphine increases the synthesis and extracellular release of NO from macrophages in Con A-stimulated splenocyte cultures. The results further suggest that the formation of the oxidant peroxynitrite through a reaction between NO and superoxide anion does not contribute significantly to the suppression of lymphocyte proliferation; instead, the activation of soluble guanylate cyclase by NO in target cells, most likely the lymphocytes, accounts more completely for the morphine-induced suppression of lymphocyte proliferation.
Aminoquinolines↗
Macrophage-derived nitric oxide is involved in the depressed concanavalin A responsiveness of splenic lymphocytes from rats administered morphine in vivo.
The present study examined the role of macrophage-derived nitric oxide in the suppressive effect of in vivo morphine administration on Con A-stimulated proliferation of splenic lymphocytes in rats. The results showed that concentrations of nitrite are significantly greater in Con A-stimulated splenocyte cultures from morphine-treated rats than in cultures from saline-treated rats, and that the depletion of macrophages from splenocyte cultures abolishes the suppressive effect of morphine on Con A-stimulated proliferation. Moreover, the addition of NG-monomethyl-L-arginine (NMMA) to Con A-stimulated splenocyte cultures attenuates the suppressive effect of morphine on mitogenic responsiveness. The addition of excess L-arginine to splenocyte cultures containing NMMA reverses the effect of NMMA and restores morphine's suppressive effect on Con A-stimulated proliferation, but the addition of D-arginine to splenocyte cultures containing NMMA does not restore the suppressive effect of morphine. Taken together, these findings demonstrate that the suppressive effect of in vivo morphine administration on Con A-stimulated proliferation of splenic lymphocytes involves macrophage-derived nitric oxide.
Animals↗
Association of genetic differences in social behavior and cellular immune responsiveness: effects of social experience.
We have recently demonstrated that selective breeding of ICR mice for differences in social behavior (i.e., high versus low levels of social isolation-induced aggression) are related to increased susceptibility to tumor development and reduced levels of natural killer (NK) cell activity. In the present investigation, we sought to extend examination of the line differences in immune status to T and B cell responsiveness. In addition, we also sought to determine if social experience contributes to line differences in immune responsiveness. A cosibial design was used to examine whether single vs group housing modified the magnitude of line differences in immune status. Compared to aggressive (NC900) mice, nonaggressive (NC100) mice had significantly lower T cell proliferative responses to concanavalin A, lower IL-2 and gamma-interferon production, as well as significantly lower NK activity. Of the various measures of cellular immune responsiveness, housing condition was found to have a significant effect only on NK activity. No significant line by housing interactions were found for any of the immune measures tested. The present data demonstrate that the genetic selection for differences in social behavior is associated with line differences in several parameters of cellular immune responsiveness. These mouse lines provide a valuable research model to examine the association between selection for genetic differences in social behavior and differences in immune responsiveness.
Animals↗
Pavlovian conditioning of morphine-induced alterations of immune status: evidence for peripheral beta-adrenergic receptor involvement.
The present studies examined the involvement of peripheral beta-adrenergic receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. Previous work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli which predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. During the training phase of these experiments, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, rats were reexposed to the conditioned stimulus prior to sacrifice. Saline or nadolol (0.002, 0.02, 0.2, or 2.0 mg/kg) was administered either prior to the training sessions or prior to the test session. Administration of nadolol prior to training did not affect the development of conditioned alterations of immune status. Conversely, nadolol administration prior to testing completely attenuated the expression of a subset of the conditioned morphine-induced changes in immune status. Taken together, these studies suggest that whereas peripheral beta-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced alterations of immune status, it is involved in the expression of a subset of these conditioned immunomodulatory effects.
Animals↗