F. B. Ross

The intrinsic antinociceptive effects of oxycodone appear to be κ-opioid receptor mediated

&NA; 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, oxycodones antinociceptive effects have a rapid onset of maximum effect (≈5–7 min compared to 30–45 min for morphine), comprise one antinociceptive phase (compared to two phases) and are of relatively short duration (≈90 min compared to ≈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 &mgr;1‐selective opioid receptor antagonist, or (ii) naltrindole, a &dgr;‐selective opioid receptor antagonist, in doses that completely attenuated the intrinsic antinociceptive effects of equipotent doses of the respective &mgr;‐ and &dgr;‐opioid agonists, morphine and enkephalin‐[d‐Pen2,5] (DPDPE). Although &bgr;‐funaltrexamine (&bgr;‐FNA) attenuated the antinociceptive effects of oxycodone (171 nmol i.c.v.), it also attenuated the antinociceptive effects of morphine and bremazocine (&kgr;‐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 &kgr;‐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 &kgr;‐opioid receptors, in contrast to morphine which interacts primarily with &mgr;‐opioid receptors.

The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices.

&NA; N‐type calcium channels modulate the release of key pro‐nociceptive neurotransmitters such as glutamate and substance P (SP) in the central nervous system. Considerable research interest has focused on the therapeutic potential of the peptidic &ohgr;‐conopeptides, GVIA and MVIIA as novel analgesic agents, due to their potent inhibition of N‐type calcium channels. Recently, the novel peptidic N‐type calcium channel blocker, AM336, was isolated from the venom of the cone snail, Conus catus. Thus, the aims of this study were to (i) document the antinociceptive effects of AM336 (also known as CVID) relative to MVIIA following intrathecal (i.t.) bolus dosing in rats with adjuvant‐induced chronic inflammatory pain of the right hindpaw and to (ii) quantify the inhibitory effects of AM336 relative to MVIIA on K+‐evoked SP release from slices of rat spinal cord. Both AM336 and MVIIA inhibited the K+‐evoked release of the pro‐nociceptive neurotransmitter, SP, from rat spinal cord slices in a concentration‐dependent manner (EC50 values=21.1 and 62.9 nM, respectively), consistent with the antinociceptive actions of &ohgr;‐conopeptides. Following acute i.t. dosing, AM336 evoked dose‐dependent antinociception (ED50≈0.110 nmol) but the doses required to produce side‐effects were an order of magnitude larger than the doses required to produce antinociception. For i.t. doses of MVIIA≤0.07 nmol, dose‐dependent antinociception was also produced (ED50≈0.016 nmol). Unexpectedly, however, i.t. doses of MVIIA>0.07 nmol, produced a dose‐dependent decrease in antinociception but the incidence and severity of the side‐effects continued to increase for all doses of MVIIA investigated, suggesting that dose‐titration with MVIIA in the clinical setting, may be difficult.

Oxycodone and morphine have distinctly different pharmacological profiles: Radioligand binding and behavioural studies in two rat models of neuropathic pain

Abstract Previously, we reported that oxycodone is a putative κ‐opioid agonist based on studies where intracerebroventricular (i.c.v.) pre‐treatment of rats with the κ‐selective opioid antagonist, nor‐binaltorphimine (nor‐BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (μ‐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 ∼3‐ to 4‐fold decrease in potency. In rat brain membranes irreversibly depleted of μ‐ and δ‐opioid binding sites, oxycodone displaced [3H]bremazocine (κ2‐selective in depleted membranes) binding with relatively high affinity whereas the selective μ‐ and δ‐opioid ligands, CTOP (d‐Phe‐Cys‐Tyr‐d‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2) and DPDPE ([d‐Pen2,5]‐enkephalin), respectively, did not. In depleted brain membranes, the κ2b‐ligand, leu‐enkephalin, prevented oxycodone’s displacement of high‐affinity [3H]bremazocine binding, suggesting the notion that oxycodone is a κ2b‐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 κ2b‐opioid agonist with a relatively low affinity for μ‐opioid receptors.

Co-administration of sub-antinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats

Abstract 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 &mgr;‐opioid agonist, this is not the case for oxycodone. Instead, our recent studies have shown that oxycodone appears to be a &kgr;‐opioid agonist (Ross and Smith, 1997). In the current study, we now show that co‐administration of sub‐antinociceptive doses of oxycodone (putative &kgr;‐opioid agonist) with morphine (&mgr;‐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

Reactions of the cis-diamminediaquaplatinum(II) cation with histidine and related molecules

Abstract 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.

Oxycodone has a distinctly different pharmacology from morphine

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, oxycodones 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).

Complexes of Peptides and Related Molecules with Diammineplatinum (II) as Models for Platinum-Protein Interactions

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.