ACEA-1328, a NMDA receptor/glycine site antagonist, acutely potentiates antinociception and chronically attenuates tolerance induced by morphine.

The effect of ACEA-1328, a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was studied on morphine-induced antinociception and tolerance in CD-1 mice using the tail flick test. To study the effect of acute administration of ACEA-1328 on morphine-induced antinociception, mice were injected with either ACEA-1328 (1, 5, and 10 mg kg(-1)) or Bis-Tris (0.2 m) immediately followed by an injection of morphine and tested for antinociception 30 min later. ACEA-1328 significantly increased the antinociceptive potency of morphine. To study the effect of chronic administration of ACEA-1328 on morphine-induced antinociception and tolerance, mice were treated, either once per day for 9 days or twice daily for 4 days, with ACEA-1328 or with the vehicle. Mice were then, within 1 min, injected daily with either morphine or saline. On the day of the test, mice were injected with only morphine and tested for antinociception 30 min later. In comparison to the acute effect of ACEA-1328, chronic treatment with the NMDA receptor/glycine site antagonist did not affect the antinociceptive potency of morphine. Chronic treatment with morphine, by both methods, produced a significant degree of tolerance. Concurrent administration of ACEA-1328 with the opioid analgesic completely blocked morphine tolerance. Our results demonstrate that acute, but not chronic, treatment with ACEA-1328 increased the antinociceptive potency of morphine. Furthermore, co-administration of the NMDA receptor antagonist with morphine abolished the development of tolerance. Overall, the data support a growing body of evidence showing that activation of the NMDA receptor plays a functional role in opioid-induced antinociception and tolerance.     

Orphanin FQ/nociceptin suppresses motor activity through an action along the mesoaccumbens axis in rats

OBJECTIVE: Intracerebroventricular administration of orphanin FQ/nociceptin (OFQ/N), the endogenous agonist ligand of the opioid receptor-like (ORL-1) receptor, decreases extracellular levels of dopamine and suppresses motor activity. The presence of the ORL-1 receptor on mesoaccumbal and nigrostriatal dopaminergic neurons raises the possibility that an action along these pathways may be one means by which OFQ/N produces motor suppression. Thus, the present study used local administration of OFQ/N into the ventral tegmental area (VTA), the substantia nigra, the nucleus accumbens and the striatum to determine the contribution of cell-body regions and terminal fields of the dopaminergic neurons to the motor-suppressant effect of OFQ/N. METHODS: Rats were implanted bilaterally with guide cannulae into one of the brain regions and tested 4 days later. First, the effect of a single dose of OFQ/N (30 microg/0.5 microL per side) on motor activity was determined after direct injection into the VTA, substantia nigra, nucleus accumbens or striatum. Rats were habituated to activity chambers for 1 hour and then injected with either artificial cerebrospinal fluid or OFQ/N into one of the brain regions, and motor activity was recorded for a further 1 hour. Next, the dose-response effect of intra-VTA or intranigral OFQ/N (3 microg or 30 microg/0.5 microL per side) on motor activity was examined. Finally, the effect of intra-VTA OFQ/N (3 microg or 30 microg/0.5 microL per side) on motor activity was determined in the presence of J-113397, an ORL-1 receptor antagonist. RESULTS: OFQ/N suppressed motor activity when injected into the VTA and to a lesser extent after direct injection into the nucleus accumbens. However, OFQ/N failed to attenuate motor activity significantly after injection into the substantia nigra or the striatum. Subsequent dose-response studies showed that OFQ/N suppressed motor activity even at a 10-fold-lower dose after intrategmental but not intranigral administration. The motor-suppressant action of intra-VTA OFQ/N was attenuated by J-113397 (1.5 microg/0.5 microL per side) administered into the VTA 10 minutes before administration of OFQ/N. CONCLUSION: Our results indicate that OFQ/N suppresses motor activity through activation of the ORL-1 receptor primarily through an action in the VTA.     

Bioactivity of a peptide derived from acetylcholinesterase: involvement of an ivermectin-sensitive site on the alpha 7 nicotinic receptor

A peptide fragment of 14 amino acids, derived from the C-terminus of acetylcholinesterase (AChE), might underlie the now well-established noncholinergic effects of the enzyme. This peptide is bioactive in a variety of systems including acute (brain slices) and chronic (organotypic culture) preparations of hippocampus, a pivotal area in Alzheimer's disease (AD); invariably, the action of the peptide is mediated specifically via an as yet unknown receptor. In this study, the allosteric alpha 7 agent, ivermectin (IVM), had a modest inhibitory effect, whilst that of the peptide was significantly more marked. However, ivermectin rendered ineffective the toxicity of high doses of the peptide, that is, when the two were co-applied, only the smaller effects of ivermectin were seen. Ivermectin, therefore, is presumably acting at a site that is identical to, or at least strongly interactive with, the normal binding site for AChE-peptide. This observation could have important implications for eventual therapeutic targeting of the action of AChE-peptide, in neurodegeneration.     

Magnetically Responsive Inorganic/Polydiacetylene Nanohybrids

A direct method for the generation of magnetically responsive conjugated polymer supramolecules is described. By immobilizing magnetite nanoparticles (MNP) on the surface of polydiacetylene (PDA) supramolecules, an inorganic/conjugated polymer hybrid system results that enables the incorporation of an important property (magnetism) to an attractive class of colorimetric PDA sensors. Benefits of this new system include: (1) ease of preparation, (2) variability in diacetylene labeling of MNPs, (3) diversity in conjugated PDA morphologies, (4) facile isolation process, and (5) immobilization of the PDA without altering the colorimetric (sensory) properties. It is demonstrated that PDA/MNP systems offer advantages in applications including film formation, separation, and sensing.     

Engaging trainees in shaping the future of health policy

This paper presents an analysis of the views and ideas generated at a recent health policy discussion for doctors in training. This provides an illustration of the creativity and enthusiasm that trainees can bring to the policy sphere by providing unique insights and a fresh perspective.     

Cytotoxic activity and chemical reactivity of cis-platinum(II) and trans-palladium(II) complexes with diethyl (pyridinylmethyl)phosphates

A series of square-planar platinum(II) and palladium(II) complexes of the formula cis-[PtCl2L2] and trans-[PdCl2L2] [L stands for diethyl (pyridin-2-ylmethyl)phosphate (2-pmOpe) or diethyl (pyridin-3-ylmethyl)phosphate (3-pmOpe) or diethyl (pyridin-4-ylmethyl)phosphate (4-pmOpe)] have been synthesized and tested in vitro for their cytotoxicity against mouse leukemia L1210 cells. The results indicated that the cis-platinum complexes showed superior activity than trans-palladium complexes, but lower in comparison to cisplatin. The chemical reactivity of the tested complexes has been determined in an in vitro NBP test. The platinum complexes exhibited very high chemical reactivity in NBP test, higher than cisplatin. The results showed no correlation between cytotoxicity and chemical reactivity for platinum complexes. Two platinum(II) complexes {cis-[PtCl2(2-pmOpe)2], cis-[PtCl2(3-pmOpe)2]} have been synthesized and characterized by IR, 1H NMR, 31P NMR, and elemental analysis.