Neuropharmacology
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Comparative Study
Role of mu- and delta-opioid receptors in the nucleus accumbens in turning behaviour of rats.
The role of mu-, delta1- and delta2-opioid receptors in the nucleus accumbens in pivoting was investigated in freely moving rats. Unilateral injections of the mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO, 1 and 2 microg) and the delta2-opioid receptor agonist, deltorphin II (1 and 2 microg), but not the delta1-opioid receptor agonist, [D-Pen(2,5)]-enkephalin (DPDPE, 1-4 microg), into the shell or the core of the nucleus accumbens significantly induced contraversive pivoting. The pivoting induced by DAMGO (2 microg) and deltorphin II (2 microg) was inhibited significantly by the mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP, 0.1 and 1 microg), and the delta2-opioid receptor antagonist, naltriben (NTB, 0.1 and 1 mg/kg, i.p.), respectively. ⋯ The contraversive pivoting elicited by the cholinergic agonist, carbachol (5 microg), into the core was inhibited by co-administration of the muscarinic M1 antagonist, pirenzepine (1 microg), but not cis(Z)-flupentixol (1 microg). The results suggest that unilateral activation of mu- or delta2-opioid, but not delta1-opioid, receptors in the core and/or shell of the nucleus accumbens elicits contraversive pivoting that requires intact dopamine D1/D2 receptors in the shell, but not intact muscarinic M1 mechanism in the core. The study also shows that delta2-opioid, but not mu- and delta1-opioid, receptors in the core and/or shell modulate the shell-specific, dopamine D1/D2 receptor mechanisms involved in the production of pivoting.
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Comparative Study
Naloxone-induced morphine withdrawal increases the number and degranulation of mast cells in the thalamus of the mouse.
Naloxone-induced jumping in morphine-dependent mice is inhibited by cromolyn, a mast cell stabilizer, suggesting that this characteristic withdrawal behavior results from degranulation of mast cells. Because withdrawal is considered as a central phenomenon, degranulation of mast cells located within the CNS may influence aspects of opioid withdrawal. The present study evaluates histologically whether naloxone, injected into opioid dependent mice, induces degranulation of mast cells. ⋯ Here, mast cells were clustered in the IGL and VPL/VPM nuclei, and redistributed from the ventromedial to the dorsolateral aspects of the Po and PF nuclei during withdrawal. Degranulation was also greater throughout the LD, LP nuclei during withdrawal. These data reveal a novel neuroimmune reaction to opioid withdrawal in the CNS.
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Comparative Study
Gabapentin may inhibit synaptic transmission in the mouse spinal cord dorsal horn through a preferential block of P/Q-type Ca2+ channels.
Gabapentin is a lipophilic analog of gamma-amino butyric acid (GABA) with therapeutic activity against certain forms of epilepsy and neuropathic pain. Despite its structural similarity to GABA, it does not bind GABAA or GABAB receptors and the mechanism, especially of its analgesic action, has remained elusive. Here, we have studied its effects on synaptic transmission mediated by the major spinal fast excitatory and inhibitory neurotransmitters, L-glutamate and glycine, in the superficial layers of the spinal cord dorsal horn, a CNS area, which is critically involved in nociception. ⋯ Gabapentin did not affect membrane currents elicited by exogenously applied glutamate or glycine arguing against a postsynaptic site of action. Selective blockade of N-type Ca2+ channels with omega-conotoxin GVIA dramatically increased and blockade of P/Q-type channels with omega-agatoxin IVA strongly attenuated inhibition of evoked synaptic transmission by gabapentin. These results show that gabapentin affects both excitatory and inhibitory spinal neurotransmission via a presynaptic mechanism which preferentially involves P/Q-type Ca2+ channels.
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Comparative Study
Neurofilament proteins and cAMP pathway in brains of mu-, delta- or kappa-opioid receptor gene knock-out mice: effects of chronic morphine administration.
Opiate addiction is associated with abnormalities of neurofilament (NF) proteins and upregulation of cAMP signaling in the brain, which may modulate neuronal plasticity. This study investigated, using gene-targeted mice lacking mu-, delta- or kappa-opioid receptors, the role of these receptors in modulating the basal activity and the chronic effects of morphine on both intracellular targets. In WT mice, chronic treatment (5 days) with morphine (20-100 mg/kg) resulted in decreases in the immunodensity of neurofilament (NF)-L in the cerebral cortex (14-23%). ⋯ In cortex and/or striatum of WT mice, chronic morphine did not induce upregulation of the main components of the cAMP signaling pathway. In contrast, chronic morphine treatment in mu-KO mice, but not in delta- or kappa-KO, resulted in a paradoxical upregulation of Galphai1/2 (12-19%), PKA (19-21%,) and phosphorylated CREB (21-73%), but not total CREB, in cortex and/or striatum. The induction of heterologous receptor adaptations in mu-KO mice may explain this paradoxical effect of morphine.
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The induction of long-term potentiation (LTP) under conditions of blockade of the N-methyl-D-aspartate receptor (NMDAR) was studied in the medial perforant path to granule cell synapse in the dentate gyrus. A small amplitude NMDAR-independent potentiation was induced by a single brief high frequency stimulation (HFS), and a summated larger LTP was induced by repeated spaced HFS. ⋯ Perfusion of the group II mGluR agonist DCG-IV induced NMDAR-independent LTP in media containing an NMDAR antagonist. The NMDAR-independent LTP induced by HFS was mediated via activation of p42/44 MAP kinase as it was blocked by the selective inhibitor PD98059.