Brain research
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The N-methyl-D-aspartate (NMDA)-type glutamate receptors in the shell region of the nucleus accumbens (ACB) have been implicated in the modulation of dopamine release and in amphetamine-induced neurotoxicity. We used electron microscopic immunocyto-chemistry to determine the anatomical sites for NMDA-mediated effects of glutamate and for their potential interactions with dopaminergic afferents identified by the presence of tyrosine hydroxylase (TH) in this region of the rat brain. Immunogold and immunoperoxidase methods were used to localize antisera against the R1 subunit of the NMDA receptor (NMDAR1) alone or combined with TH. ⋯ The TH-immunoreactive terminals were more often seen apposed to NMDA-immunoreactive astrocytic processes and dendrites. These results provide the first ultrastructural evidence for presynaptic modulation of dopamine release by NMDA receptors in the shell of the nucleus accumbens. They also indicate that NMDA receptors modulate postsynaptic neurons receiving input from the dopaminergic afferents and suggest a previously unsuspected functional association involving glial NMDA receptors and dopaminergic afferents in this brain region.
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This report describes the effects of intravenously administered agonists and antagonists at mu-, delta 1- and delta 2-opioid receptors on the A delta- and C-fiber-evoked responses of trigeminal nociceptive neurons in anesthetized rats. Extracellular single unit recordings were made from 61 nociceptive neurons (23 NS, 38 WDR) in the superficial and 37 nociceptive neurons (3 NS, 34 WDR) in the deeper dorsal horn of the medulla (trigeminal nucleus caudalis). Administration of either the delta 1-receptor agonist [D-Pen2,5]enkephalin (DPDPE; 0.05-2 mg/kg), the delta 2-receptor agonist [D-Ala2, Glu4]deltorphin (DELT; 1-2 mg/kg) or the mu-receptor agonist [D-Ala2, N-MePhe4, Gly5-ol]enkephalin (DAMGO; 0.05-1 mg/kg) inhibited the A delta- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn. ⋯ A smaller dose of NTB (0.3 mg/kg), which failed to reverse the effects of DPDPE in 100% (4/4) of neurons, effectively antagonized the effects of DELT in 100% (6/6) of neurons. The inhibitory action of DAMGO was completely antagonized by naloxone (0.2 mg/kg) in 100% (6/6) of neurons. The results of the present investigation suggest that: (1) mu-, delta 1- and delta 2-opioid receptors play an important role in the inhibitory modulation of the A delta- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla; (2) selective inhibition of the C-fiber-evoked responses by activation of opioid receptors may account for the opioid-mediated selective suppression of second or persistent pain as compared to first pain; and (3) NTB, in a limited dose range, can discriminate between delta 1- and delta 2-opioid receptor subtypes.
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It has been demonstrated in guinea pigs that nitric oxide synthase (NOS) activity is increased in late pregnancy in some peripheral tissues and in the cerebellum. To determine whether similar changes would be observed in areas of the brain known to play a role in parturition, staining for NADPH-diaphorase, a histochemical marker of NOS synthase, in the paraventricular (PVN) and supraoptic nuclei (SON) was compared among ovariectomized, virgin and late pregnant rats. The number of cells showing dense staining for NADPH-diaphorase increased in both the SON and PVN in late pregnancy compared to that observed in virgin and ovariectomized females. Thus, changes in reproductive state are associated with changes in NADPH-diaphorase staining in areas of the brain that are intimately involved in the control of reproductive function.
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Cultured cerebellar granule cells and cerebellar slices from neonatal rats have been widely used to examine the biochemistry of excitatory amino acid-induced cell death mediated in part by the activation of NMDA receptors. However, the NMDA subunit stoichiometry, producing functional NMDA receptors is different in cultured granule cells, neonatal and adult rat cerebellum as compared to the NMDA receptors in forebrain regions. We have used the L-2-chloropropionic acid (L-CPA) (750 mg/kg) model of NMDA-mediated selective cerebellar granule cell necrosis in vivo to examine the role of the glycine binding site and possible effect of the NR2C subunit (which is largely expressed only in the cerebellum) on granule cell necrosis. ⋯ In conclusion, we demonstrated that NMDA open channel blockade and glutamate antagonists can provide full neuroprotection against the L-CPA-induced granule cell necrosis. The failure of the glycine partial agonist and antagonists to provide any neuroprotection against L-CPA-induced neurotoxicity in the cerebellum contrast with their neuroprotective efficacy in other animal models of excitatory amino acid-induced cell death in forebrain regions in vivo. We therefore suggest that the glycine site plays a lesser role in modulating NMDA receptor function in the cerebellum and may explain why cells expressing NMDA receptors composed of NR1/NR2C subunits are particularly resistant to excitatory amino acid-induced neurotoxicity.
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The present series of experiments were designed to examine a potential role for central descending pain facilitatory systems in mediating secondary hyperalgesia produced by topical application of mustard oil and measuring the nociceptive tail-flick reflex in awake rats. Topical application of mustard oil (100%) to the lateral surface of the hind leg produced a facilitation of the tail-flick reflex that was significantly reduced in spinal transected animals. Mustard oil hyperalgesia was also inhibited in animals that had received electrolytic lesions in the rostral ventromedial medulla (RVM). ⋯ Similar to spinal proglumide, microinjection of the neurotensin antagonist SR48692 (3.5 micrograms) into the RVM blocked mustard oil hyperalgesia and inhibited the tail-flick reflex. These data suggest that secondary hyperalgesia produced by mustard oil is mediated largely by a central, centrifugal descending pain facilitatory system which involves neurotensin in the RVM and spinal CCK (via CCKB receptors). The inhibition of the tail-flick reflex produced by mustard oil following spinal or supraspinal administration of receptor antagonists suggests concurrent activation of central descending facilitatory and inhibitory systems.