Biomedical subjects

K A Carrigan

Publications and source records attributed to K A Carrigan.

4 recordsLinked to original sources

PubMed2001

Morphine-6 beta-glucuronide induces potent immunomodulation.

The effect of morphine administration on immune parameters is well documented. However, there exists a limited knowledge of the effect of morphine's metabolites on immune status. The present study examines the immunomodulatory effects of the morphine metabolite, morphine-6 beta-glucuronide (M6G), in the rat and provides further evaluation of the antinociceptive effects of M6G. Animals were administered phosphate-buffered saline (PBS) or M6G in doses of 1.0, 3.16, or 10.0 mg/kg (subcutaneous (s.c.)) or 0.1, 0.316, or 1.0 microgram (intracerebroventricular (i.c.v.)). Animals were tested for antinociception in the warm water tail-withdrawal procedure. In a separate set of animals, assessments of splenic natural killer cell activity, lymphocyte proliferative responses to mitogenic stimulation, and production of interferon-gamma were made 1 h following the s.c. or i.c.v. administration of M6G. The results show that M6G induced potent antinociception that was evident for at least 120 min following administration. M6G also produced decreases in natural killer cell activity, lymphocyte proliferation, and interferon-gamma production 1 h following both routes of administration. The difference in potency between immune alterations induced by subcutaneous vs. intracerebroventricular administration suggest central mediation of the immunomodulatory properties of M6G. Thus, M6G produces significant antinociception and immunomodulation in the rat. These findings demonstrate potent immunomodulatory properties of a metabolite of morphine, 1M6G.

Adjuvants, Immunologic↗

PubMed2001

Morphine-6beta-glucuronide modulates the expression of inducible nitric oxide synthase.

The immunomodulatory effects of morphine are well established; however, suprisingly little is known about the immunomodulatory properties of the major metabolites of morphine. The present study tests the hypothesis that expression of inducible nitric oxide synthase (iNOS) is modulated by the administration of the morphine metabolite, morphine-6beta-glucuronide. The initial study using rats shows that morphine-6beta-glucuronide administration (0, 1.0, 3.163, 10 mg/kg s.c.) results in a pronounced reduction in lipopolysaccharide (LPS)-induced expression of iNOS (inducible nitricoxide synthease) in spleen, lung, and liver tissue as measured by western blotting. Morphine-6beta-glucuronide also produces a reduction in the level of plasma nitrite/nitrate, the more stable end-product of nitric oxide degradation. In a subsequent study, administration of the opioid receptor antagonist, naltrexone (0.1 mg/kg) prior to the injection of morphine-6beta-glucuronide (10 mg/kg) blocks the morphine-6beta-glucuronide induced reduction of iNOS expression and plasma nitrite/nitrite levels indicating that the effect is mediated via the opioid-receptor. This study provides the first evidence that morphine-6beta-glucuronide alters the expression of iNOS.

Animals↗

PubMed2000

Naltrexone administration attenuates surgery-induced immune alterations in rats.

Surgery is a commonly performed procedure which produces substantial alterations in immune function in both humans and animals. To better understand the mechanism of surgery-induced immunomodulation, the present study investigated the effect of the opioid antagonist naltrexone on surgery-induced immune alterations in rats. Based on previous investigations in our laboratory, rats underwent a 6-cm laparotomy with no internal manipulation and immunological assessments were completed 24 h following the surgical procedure. Naltrexone was administered at the time of surgery and every 4 h thereafter until immune assessment. Results showed that naltrexone attenuated the surgery-induced decrease in natural killer cell cytotoxicity, B-cell proliferation, T-cell proliferation, and production of the cytokine IFN-gamma. These results are among the first to show that pharmacological antagonism of opioid receptors can prevent deleterious immune changes in the postoperative state, suggesting a detrimental role of the endogenous opioids in surgical procedures.

Abdomen↗

PubMed2000

Endomorphin-1 induces antinociception without immunomodulatory effects in the rat.

RATIONALE: Although there is evidence that central opioid receptors are involved in immunomodulation, it has been only recently that an endogenous agonist, designated endomorphin-1, possessing high selectivity and affinity for the mu opioid receptor has been identified. OBJECTIVE: The present study assesses the immunomodulatory effects of endomorphin- in the rat and provides further evaluation of the antinociceptive effects of endomorphin-1. METHODS: Rats were surgically implanted with cannulae directed at the lateral cerebral ventricle. Animals received vehicle or endomorphin-1 at doses of 31.63 or 56.23 microg (ICV) and were tested for antinociception in two different assays, the warm water tail withdrawal procedure and the hotplate assay. Additional studies assessed the effect of naltrexone on the antinociception produced by endomorphin-1 in both antinociceptive assessments. Assessments of immune status following endomorphin-1 treatment included measurements of splenic natural killer cell activity, production of interferon-y, and lymphocyte proliferative responses to mitogenic stimulation by Con-A, LPS, and the microbial superantigen, TSST-1. RESULTS: Endomorphin-1 induced significant and naltrexone reversible antinociception 30 and 60 min following drug administration, as measured by the hotplate assay and warm water tail withdrawal procedure. In marked contrast, endomorphin-1 did not produce immunomodulatory effects up to 120 min following ICV administration. CONCLUSIONS: Endomorphin-1 produces antinociception but does not induce immunomodulatory effects in the rat. These findings suggest that it is possible to develop therapeutic strategies for separating antinociception and immunomodulatory properties through the mu opioid receptor.

Analgesics, Opioid↗