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Background: Diabetes in humans induces chronic complications such as cardiovascular damage, cataracts and retinopathy, nephropathy and polyneuropathy. The most common animal model of human diabetes is streptozotocin (STZ)-induced diabetes in the rat. Methods: This project assessed cardiovascular, ocular and neuropathic changes over a period of 24 weeks post STZ administration in rats. Results: STZ-diabetic rate (n=96) showed stable signs of diabetes (hyperglycaemia, increased water and food intake with no increase in bodyweight): 52% of untreated STZ-diabetic rats (n=50) survived 24 weeks after STZ administration. STZ-diabetic rats were normotensive with slowly developing systolic and diastolic dysfunction and an increased ventricular stiffness. Ventricular action potential durations were markedly prolonged. STZ-diabetic rats developed stable tactile allodynia. Cataracts developed to presumed blindness at 16 weeks but proliferative retinopathy was not observed even after 24 weeks. Conclusion: The chronic STZ-diabetic rat mimics many but not all of the chronic complications observed in the diabetic human. The chronic STZ-diabetic rat may be a useful model to test therapeutic approaches for amelioration of chronic diabetic complications in humans.

The reaction of cis-[Pt(NH3)2(H2O)2]2+ (1) with histidine (H3his+) at pH 2–3 gave initially complexes with histidine bound through carboxylate only, then, after standing, the complex containing an amine nitrogen (NA), carboxylate oxygen-chelate ring [Pt(NH3)2(H2-his-NA,O)]2+. Increasing the pH to 8–9 caused loss of one imidazole proton, followed by isomerization to the species with a imidazole N(3), NA-chelate ring, [Pt(NH3)2(Hhis-NA,N(3))]. From the variation of NMR parameters with pH, pKa for loss of the last imidazole proton was determined (11.2 ± 0.1). Histidine methyl ester and histidinamide each reacted slowly with 1 at pH 5.5 to give the NA,N(3)-chelate complex. With N-(histidyl)glycine the initial complexes at pH 5 contained the ligand bound only through carboxylate, but a NA,N(3)-chelate complex then formed. With an excess of 1, a second diammineplatinum moiety was bound, initially through the free carboxylate, then chelated by carboxylate and peptide nitrogen. With N-acetylhistidine and N-(β-alanyl)histidine at pH 4–5, the initial complexes also contained carboxylate-bound ligands, then a chelate ring was formed involving carboxylate and the deprotonated amide or peptide nitrogen, NA. With N-(glycyl)histidine, more complex reactions involving the terminal nitrogen atom also occurred. In alkaline solution, these NA,O-chelate complexes reacted slowly to form a dinuclear complex with one ligand bound to one Pt atom through NA and N(3), and to the second platinum through N(1) of bridging imidazolate. The second ligand was bound monodentate to the second platinum through NA.

Previously, we reported that oxycodone is a putative kappa-opioid agonist based on studies where intracerebroventricular (i.c.v.) pre-treatment of rats with the kappa-selective opioid antagonist, nor-binaltorphimine (nor-BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (mu-selective antagonist) produced the opposite effects. In the present study, we used behavioural experiments in rat models of mechanical and biochemical nerve injury together with radioligand binding to further examine the pharmacology of oxycodone. Following chronic constriction injury (CCI) of the sciatic nerve in rats, the antinociceptive effects of intrathecal (i.t.) oxycodone, but not i.t. morphine, were abolished by nor-BNI. Marked differences were found in the antinociceptive properties of oxycodone and morphine in streptozotocin (STZ)-diabetic rats. While the antinociceptive efficacy of morphine was abolished at 12 and 24 weeks post-STZ administration, the antinociceptive efficacy of s.c. oxycodone was maintained over 24 weeks, albeit with an approximately 3- to 4-fold decrease in potency. In rat brain membranes irreversibly depleted of mu- and delta-opioid binding sites, oxycodone displaced [(3)H]bremazocine (kappa(2)-selective in depleted membranes) binding with relatively high affinity whereas the selective mu- and delta-opioid ligands, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) and DPDPE ([D-Pen(2,5)]-enkephalin), respectively, did not. In depleted brain membranes, the kappa(2b)-ligand, leu-enkephalin, prevented oxycodone's displacement of high-affinity [(3)H]bremazocine binding, suggesting the notion that oxycodone is a kappa(2b)-opioid ligand. Collectively, the present findings provide further support for the notion that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations. Oxycodone appears to act as a kappa(2b)-opioid agonist with a relatively low affinity for mu-opioid receptors.

Our previous studies indicate that oxycodone is a putative kappa-opioid agonist, whereas morphine is a well documented micro-opioid agonist. Because there is limited information regarding the development of tolerance to oxycodone, this study was designed to 1) document the development of tolerance to the antinociceptive effects of chronically infused i.v. oxycodone relative to that for i. v. morphine and 2) quantify the degree of antinociceptive cross-tolerance between morphine and oxycodone in adult male Dark Agouti (DA) rats. Antinociceptive testing was performed using the tail-flick latency test. Complete antinociceptive tolerance was achieved in 48 to 84 h after chronic infusion of equi-antinociceptive doses of i.v. oxycodone (2.5 mg/24 h and 5 mg/24 h) and i.v. morphine (10 mg/24 h and 20 mg/24 h, respectively). Dose-response curves for bolus doses of i.v. and i.c.v. morphine and oxycodone were produced in naive, morphine-tolerant, and oxycodone-tolerant rats. Consistent with our previous findings that oxycodone and morphine produce their intrinsic antinociceptive effects through distinctly different opioid receptor populations, there was no discernible cross-tolerance when i.c.v. oxycodone was given to morphine-tolerant rats. Similarly, only a low degree of cross-tolerance (approximately 24%) was observed after i.v. oxycodone administration to morphine-tolerant rats. By contrast, both i.v. and i.c.v. morphine showed a high degree of cross-tolerance (approximately 71% and approximately 54%, respectively) in rats rendered tolerant to oxycodone. Taken together, these findings suggest that, after parenteral but not supraspinal administration, oxycodone is metabolized to a mu-opioid agonist metabolite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine.

Oxycodone and morphine are structurally related, strong opioid analgesics, commonly used to treat moderate to severe pain in humans. Although it is well-established that morphine is a mu-opioid agonist, this is not the case for oxycodone. Instead, our recent studies have shown that oxycodone appears to be a kappa-opioid agonist (Ross and Smith, 1997). In the current study, we now show that co-administration of sub-antinociceptive doses of oxycodone (putative kappa-opioid agonist) with morphine (mu-opioid agonist) to rats by both the intracerebroventricular and by systemic routes (intraperitoneal and subcutaneous), results in markedly increased (synergistic) levels of antinociception. Behaviourally, rats co-administered sub-antinociceptive doses of oxycodone and morphine were similar to control rats dosed with saline, whereas rats that received equi-potent doses of either opioid alone, were markedly sedated. These results suggest that co-administration of sub-analgesic doses of oxycodone and morphine to patients may provide excellent pain relief with a reduction in opioid-related CNS side-effects. Controlled clinical trials in appropriate patient populations are required to evaluate this possibility.(1)

Our previous studies in the Sprague-Dawley rat showed that the intrinsic antinociceptive effects of oxycodone are naloxone reversible in a manner analogous to morphine but that in contrast to morphine, oxycodone's antinociceptive effects have a rapid onset of maximum effect (approximately 5-7 min compared to 30-45 min for morphine), comprise one antinociceptive phase (compared to two phases) and are of relatively short duration (approximately 90 min compared to approximately 180 min). In the present study, administration of a range of selective opioid receptor antagonists has shown that the intrinsic antinociceptive effects of oxycodone (171 nmol) are not attenuated by i.c.v. administration of (i) naloxonazine, a mu1-selective opioid receptor antagonist, or (ii) naltrindole, a delta-selective opioid receptor antagonist, in doses that completely attenuated the intrinsic antinociceptive effects of equipotent doses of the respective mu- and delta-opioid agonists, morphine and enkephalin-[D-Pen(2,5)] (DPDPE). Although beta-funaltrexamine (beta-FNA) attenuated the antinociceptive effects of oxycodone (171 nmol i.c.v.), it also attenuated the antinociceptive effects of morphine and bremazocine (kappa-opioid agonist) indicative of non-selective antagonism. Importantly, the antinociceptive effects of oxycodone (171 nmol i.c.v.) were markedly attenuated by the prior i.c.v. administration of the selective kappa-opioid receptor antagonist, norbinaltorphimine (nor-BNI), in a dose (0.3 nmol) that did not attenuate the antinociceptive effects of an equipotent dose of i.c.v. morphine (78 nmol). Taken together, these data strongly suggest that the intrinsic antinociceptive effects of oxycodone are mediated by kappa-opioid receptors, in contrast to morphine which interacts primarily with mu-opioid receptors.

Oxycodone is a potent opioid agonist that has been in clinical use for many decades. However, it has only recently been appreciated that oxycodone has a distinctly different pharmacology from that of morphine. Importantly, when administered directly into the lateral ventricle of the rat brain, oxycodone produces dose-dependent, naloxone-reversible pain relief in an acute pain model, indicating that oxycodone itself has intrinsic anti-nociceptive effects (Leow & Smith, 1994). However, oxycodone's intrinsic pain-relieving effects are not attenuated by naloxonazine (-selective opioid antagonist) in a dose that completely blocks the anti-nociceptive effects of an equi-analgesic dose of morphine. Furthermore, the anti-nociceptive effects of intracerebroventricular (icv) oxycodone are completely attenuated by nor-binaltorphimine (-selective opioid antagonist) in a dose that has no significant effect on the levels of anti-nociception evoked by an equi-effective dose of morphine (Ross & Smith, 1997).

There is ample evidence that the primary target of platinum anti-tumor drugs is DNA, which has caused much interest in the chemistry of platinum complexes of nucleobases.1 If, however, one wishes fully to understand the biological chemistry of the platinum compounds, it is also necessary to consider their interaction with other potential ligands which are present in vivo. Among the more important of these are proteins, peptides, and amino acids. Reaction of platinum drugs with these compounds may have the following effects:2 (i) To the extent that the platinum compounds react with such molecules, they are prevented from reacting with the target DNA. (ii) Some of the toxic side-effects of platinum drugs are due to platinum-protein interactions. (iii) Some forms of resistance of tumor cells toward platinum drugs may be due to enhanced coordination by peptides and proteins.