Interference with tissue factor prolongs intrahepatic islet allograft survival in a nonhuman primate marginal mass model.

BACKGROUND: Tissue factor (TF) expression on islets can result in an instant blood-mediated inflammatory reaction (IBMIR) that contributes to early islet loss. We tested whether peritransplant protection of islets from IBMIR with a monoclonal anti-TF antibody (CNTO859) would enhance engraftment in our nonhuman primate marginal mass model. METHODS: Each of six pairs of cynomolgus monkeys (CM) with streptozotocin-induced diabetes was closely matched for metabolic control and was transplanted with 5,000 IEQ/kg allogeneic, ABO-compatible islets from the same donor under the cover of steroid-free immunosuppression. For each pair, experimental animals received islets cultured with 20 microg/mL anti-TF and were dosed with 6 mg/kg anti-TF intravenously, 10-25 min before islet infusion; control monkeys received an equal number of islets from the same preparation cultured without anti-TF and no in vivo treatment. RESULTS: Early fasting C-peptide (CP) values were different between (P<0.01), but not within, pairs and correlated with in vitro functional capacity of islets as assessed by perifusion (r=0.60; P=0.022). Compared to their matched controls, experimental animals had decreased posttransplant markers of coagulation, higher fasting CP levels (1 month posttransplant and end of study) and prolonged graft function. CONCLUSIONS: These data suggest that pretreatment of islets and the recipient with anti-TF may limit the effects of IBMIR, thereby enhancing islet engraftment and survival.

A role for mu opioid receptors in cocaine-induced activity, sensitization, and reward in the rat.

RATIONALE: Considerable evidence suggests that the endogenous opioid system plays a role in mediating the behavioral effects of psychostimulants. Opioidergic drugs have been shown to have profound effects on cocaine-induced behavioral sensitization and conditioned reward. However, the role specifically of the mu opioid receptor in this regard is unclear as most previous pharmacological studies have used nonselective opioid receptor ligands. OBJECTIVES: The objective of this series of experiments was to elucidate the role of mu opioid receptors in the behavioral effects of cocaine in the rat. MATERIALS AND METHODS: Adult male rats were used to assess the effects of the selective mu opioid receptor antagonist D: -Phe-Cys-Tyr-D: -Trp-Arg-Thr-Pen-Thr (CTAP) on acute hyperactivity, locomotor sensitization, and conditioned place preference induced by cocaine. Intracerebroventricular administration of CTAP, 4 microg, was paired with peripheral injections of cocaine, 10-15 mg/kg. RESULTS: Mu receptor blockade significantly attenuated cocaine-induced hyperactivity, as well as the development of behavioral sensitization. Pretreatment with CTAP also prevented the development of conditioned place preference to cocaine. Administration of CTAP alone had neither effect on locomotor activity nor did it demonstrate aversive or rewarding properties. CONCLUSIONS: These results suggest that activation of mu opioid receptors by endogenous opioids is an important contributor to cocaine-induced hyperactivity and the development of behavioral sensitization and conditioned reward.

Cocaine-induced mu opioid receptor occupancy within the striatum is mediated by dopamine D2 receptors.

Previous studies by our laboratory have demonstrated that the mu opioid receptor antagonist, CTAP, blocks the rewarding effects of cocaine when it is injected directly into the nucleus accumbens or ventral tegmental area (VTA). This finding suggests that cocaine is causing the release of endogenous opioid peptides which activate mu opioid receptors within the nucleus accumbens and VTA. The purpose of the present study was to characterize the dose-response and time-course of mu receptor occupancy following systemic cocaine administration and to determine if release of endogenous opioids by cocaine is mediated by activation of D1 or D2 dopamine receptors. Quantitative in vitro receptor autoradiography was used to measure the regional displacement of (3)H-DAMGO binding following cocaine administration. Adult male Sprague-Dawley rats were given intraperitoneal (i.p.) injections of cocaine and their brains were removed at various times and prepared for mu opioid receptor quantitation. To determine the role of dopamine D1 and D2 receptors in the effect of cocaine on mu receptor occupancy, rats were injected with the selective D1 or D2 receptor antagonists SCH23390 or eticlopride prior to cocaine. For all studies, (3)H-DAMGO binding to mu opioid receptors was measured in the nucleus accumbens, caudate putamen, frontal cortex, olfactory tubercle and VTA. Results demonstrate that cocaine administration caused a time- and dose-dependent reduction in (3)H-DAMGO binding within the nucleus accumbens core and shell. The reduction in mu receptor binding was attenuated by pretreatment with eticlopride. These results suggest that cocaine, acting via D2 dopamine receptors, can cause the release of an endogenous opioid peptide that binds to mu opioid receptors within the nucleus accumbens.