Neuropharmacology
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There is poor experimental evidence concerning the effects of anesthetic doses of the non-competitive NMDA receptor antagonist ketamine on rodents' memory abilities. The present study was designed to investigate a) the long-term consequences of anesthetic ketamine on rats' non-spatial and spatial recognition memory; b) to evaluate whether or not these effects are related to the hypothermic properties of ketamine and c) to detect when the (amnestic) effects of ketamine on recognition memory were extinguished. ⋯ Pre-training administration of ketamine (100 mg/kg; i.p.) disrupted animals' performance in the object location task and to some extent also in the object recognition paradigm indicating that anesthetic ketamine impaired both spatial and non-spatial recognition memory. Hypothermia-induced by this NMDA receptor antagonist and the type (spatial vs. non-spatial) of the behavioral paradigm utilized seem to affect rats' recognition memory recovery.
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Vulnerability to the addictive effects of drugs of abuse varies among individuals, but the biological basis of these differences are poorly known. This work tries to increase this knowledge by comparing the brain proteome of animals with different rate of extinction of cocaine-seeking behaviour. To achieve this goal, we used a place-preference paradigm to separate Sprague Dawley rats in two groups: rats that extinguished (E) and rats that did not extinguish (NE) cocaine-seeking behaviour after a five-day period of drug abstinence. ⋯ When comparing E SAL and NE SAL animals we found significant differences in the expression level of 5 proteins: ATP synthase subunit alpha, fumarate hydratase, transketolase, NADH dehydrogenase [ubiquinone] flavoprotein 2 and glutathione transferase omega-1. A single injection of COC differently alters the NAC proteome of E and NE rats; thus in E COC animals there was an alteration in the expression of 6 proteins, including dihydropyrimidinase-related protein 2 and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10; whereas in NE COC rats 9 proteins were altered (including alpha-synuclein, peroxiredoxin-2 and peroxiredoxin-5). These proteins could be potential biomarkers of individual vulnerability to cocaine abuse and may be helpful in designing new treatments for cocaine addiction.
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Persistent inflammatory nociception increases levels of endogenous opioids with affinity for delta opioid receptors in the ventromedial medulla and enhances the antinociceptive effects of the mu opioid receptor (MOPr) agonist [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) [Hurley, R. W., Hammond, D. L., 2001. ⋯ Microinjection of the MOPr antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) in the LC did not exacerbate hyperalgesia in the ipsilateral hindpaw or produce hyperalgesia in the contralateral hindpaw of CFA-treated rats. The downregulation in MOPr is therefore unlikely to result from the induction of endogenous opioid tolerance in the LC. These results indicate that persistent inflammatory nociception alters the antinociceptive actions of MOPr agonists in the CNS by diverse mechanisms that are nucleus specific and likely to have different physiological implications.
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Both the clinical tolerability and the symptomatic effects of memantine in the treatment of Alzheimer's disease have been attributed to its moderate affinity (IC(50) around 1 microM at -70 mV) for NMDA receptor channels and associated fast, double exponential blocking/unblocking kinetics and strong voltage-dependency. Most of these biophysical data have been obtained from rodent receptors. Some substances show large species-specific differences, so using human rather than rodent receptors and tissue may highlight important differences in the effects of drugs. ⋯ Moreover, the rapid double exponential blocking kinetics (e.g. at 10 microM - onset tau(fast)=273+/-25 ms (weight 69%), onset tau(slow)=2756+/-296 ms, offset tau(fast)=415+/-82 ms (weight 38%) offset tau(slow)=5107+/-1204 ms) and partial untrapping (around 20%) previously reported for memantine on rodent receptors were confirmed for human receptors. Ketamine showed similar potency (IC(50) at -70 mV of 0.71+/-0.03 microM, Hill=0.84+/-0.02) but somewhat less pronounced voltage-dependency (delta=0.79+/-0.04), slower, single exponential kinetics (ketamine: k(on)=0.15+/-0.05 x 10(6)M(-1)s(-1), k(off)=0.22+/-0.05 s(-1)c.f. memantine following normalization k(on)=0.32+/-0.11 x 10(6)M(-1)s(-1), k(off)=0.53+/-0.10s(-1)) and was fully trapped. The present data closely match previously reported data from studies in rodent receptors and suggest that the proposed mechanism of action of memantine in Alzheimer's disease as a fast, voltage-dependent open-channel blocker of NMDA receptors can be confirmed for human NMDA receptors.
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Nitric oxide synthase (NOS) isoforms and NO downstream signal pathways involved spinally in the maintenance of thermal and mechanical hypersensitivity were assessed in a mouse model of neuropathic pain developing after partial ligation of the sciatic nerve. Intrathecal injection of the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME), the highly selective neuronal NOS (nNOS) inhibitor N(omega)-propyl-l-arginine and the potent selective inducible NOS (iNOS) inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine hydrochloride (AMT) exerted dose-dependent analgesic effects on thermal and mechanical hypersensitivity, which were assessed by the plantar and von Frey tests, respectively, suggesting that both nNOS and iNOS participate in producing NO to maintain neuropathic pain. ⋯ Finally, intrathecal injection of phenyl-N-tert-butylnitrone (PBN), a reactive oxygen species (ROS) scavenger, ameliorated thermal and mechanical hypersensitivity, thus further confirming the importance of ROS including NO and superoxide in the maintenance of neuropathic pain. Together, the present results demonstrate that NO, produced presumably via nNOS and iNOS in the spinal cord, mediates the maintenance of neuropathic pain following peripheral nerve injury through both the NO-cGMP-PKG and the NO-peroxynitrite pathways.