Neuroreport
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The present study tested the hypothesis that endogenous opioid peptides acting at the delta-opioid receptor (DOR) in the rostral ventromedial medulla (RVM) contribute to the antinociception elicited by the mu-opioid receptor (MOR) agonist DAMGO in the midbrain periaqueductal gray (PAG). Following microinjection of DAMGO into the PAG, either the highly selective DOR antagonist TIPP[psi] or the DOR2 antagonist naltriben (NTB) was microinjected into the RVM. Both TIPP[psi] (1.0 microg) and NTB (5.0 ng) significantly attenuated the analgesic effect of PAG DAMGO but had no effect when given before PAG saline. These results confirm and extend previous studies suggesting that PAG mu-opioids activate a descending system with a DOR mediated endogenous opioid link in the RVM.
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The intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) reduced pain-related behaviors after peripheral nerve or spinal cord injury in rats. The endogenous ligand adenosine is clinically available and has been tested i.t. as an analgesic. Thus, we set out to investigate whether i.t. adenosine could reduce allodynia in a model of central pain in spinally injured rats. ⋯ R-PIA at 10 nmol markedly alleviated allodynia in the same animals. The lack of effect by exogenous adenosine may be due to pharmacokinetic or pharmacodynamic reasons. Alternatively, adenosine may have reduced affinity and selectivity towards the A1-receptors which may be important for the antiallodynic effect.
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Randomized Controlled Trial Clinical Trial
Noradrenergic modulation of cognitive flexibility in problem solving.
Stress causes impaired performance on tests of creativity. Drugs that block beta-adrenergic receptors improve test performance in patients with test anxiety. Furthermore, catecholamine precursors (L-DOPA) reduce the flexibility of semantic networks. ⋯ Eighteen normal subjects undertook three problem solving tasks (number series, shape manipulation and anagrams) 45 min after propranolol, placebo and ephedrine. On the task that appeared to rely most heavily on cognitive flexibility (anagrams), subjects who were most able to solve these problems demonstrated significantly shorter solution times (logarithmic scores) after propranolol than after ephedrine. This suggested that the noradrenergic system exerts a modulatory effect on cognitive flexibility in problem solving.
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The possibility that ectopic purinergic sensitivity develops following peripheral nerve injury was investigated in chronic constriction injury (CCI). Spontaneous firing of A-fibers originated from the injury site or from sensory endings of afferents in the contralateral sciatic nerve. ⋯ Neither the alpha-adrenoreceptor antagonist phentolamine nor the cyclooxygenase inhibitor indomethacin attenuated the ATP-evoked effect. We conclude that a novel ectopic purinergic sensitivity mediated by P2 receptors develops at sites of the CCI of nerves in the rat, which may contribute to neuropathic pain.
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Clinical Trial
Decreased calmodulin-NR1 co-assembly as a mechanism for focal epilepsy in cortical dysplasia.
The NMDA receptor is one of the ionotropic glutamate receptors essential for excitatory neurotransmission. The NMDAR1 subunit is inactivated by direct interaction with calmodulin. ⋯ In all patients, the co-assembly of calmodulin and NMDAR1 was decreased in epileptogenic dysplastic cortex compared with normal appearing non-epileptogenic cortex, while there was no significant difference in the total protein levels of calmodulin or NMDAR1 between the two EEG groups. These results suggest that decreased calmodulin-NMDAR1 co-assembly is a cellular mechanism that contributes to hyperexcitability in dysplastic cortical neurons and in focal seizure onsets.