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R M Caudle

Publications and source records attributed to R M Caudle.

28 records · Page 2Linked to original sources
PubMed1992

Endogenous opioid regulation of norepinephrine release in guinea pig hippocampus.

Release of endogenous norepinephrine was detected in guinea pig hippocampal slices using a radioligand displacement assay. Focal electrical stimulation released endogenous norepinephrine and caused a calcium-dependent reduction in specific [3H]propranolol binding at beta-adrenergic receptors in the brain slice. The mu-opioid agonist PL017 decreased norepinephrine release, and the inhibition by PL017 could be blocked by the opioid antagonist naloxone. Endogenous opioid peptides concomitantly released by tissue stimulation also decreased norepinephrine release in a naloxone-sensitive manner. These results support the hypothesis that endogenous opioids can regulate excitability in the hippocampus by presynaptic modulation of norepinephrine release.

Animals↗
PubMed1992

Kappa-opioids decrease excitatory transmission in the dentate gyrus of the guinea pig hippocampus.

In the guinea pig hippocampus, kappa 1-opioid binding sites were primarily localized in the molecular layer of the dentate gyrus as shown by autoradiography using either the kappa 1-selective radioligand 3H-U69,593 or the nonselective radioligand 3H-diprenorphine in the presence of unlabeled mu- and delta-blocking ligands. In this region, the electrophysiological effects of kappa 1-receptor activation were identified using extracellular and intracellular recordings of dentate granule cell responses. The amplitude of the extracellularly recorded population spike was reduced by U69,593 with an EC50 of 26 nM; this effect was reversible and blocked by the opioid antagonist naloxone. The kappa 1-selective antagonist norbinaltorphimine also blocked the effect of U69,593 with an apparent equilibrium dissociation constant (Ki) of 0.26 nM determined by Schild analysis in the physiologic assay. This value agreed well with the Ki for norbinaltorphimine at kappa 1-binding sites measured by radioligand binding displacement (0.24 nM). These results indicate that the electrophysiologic response observed was likely mediated by kappa 1-receptors. As seen with U69,593, dynorphin B, an endogenous opioid peptide that is present in the dentate gyrus, also inhibited the population spike response. mu- and delta-selective opioid agonists had no effect on the amplitude of the maximally evoked response. Intracellular recordings of dentate granule cells showed no direct effects of U69,593 on the granule cells themselves. However, analysis of synaptic potentials revealed that U69,593 significantly reduced the amplitude of glutaminergic EPSPs evoked by afferent stimulation without affecting IPSP amplitudes. The specific effect of U69,593 application on granule cell EPSPs indicates that presynaptic kappa 1-receptor activation inhibits glutamate release from perforant path terminals in the molecular layer of the dentate gyrus. These results suggest that endogenous dynorphins present in the granule cells may act as feedback inhibitors of the major excitatory input to the dentate gyrus.

Action Potentials↗
PubMed1991

Endogenous opioids released from perforant path modulate norepinephrine actions and inhibitory postsynaptic potentials in guinea pig CA3 pyramidal cells.

The stimulus parameters needed for the release of endogenous opioid peptides were investigated using an in vitro radioligand displacement assay in living guinea pig hippocampal slices. Electrical stimulation of the enkephalin-containing fibers in the perforant path caused the release of endogenous opioid peptides and the subsequent displacement of [3H]-[D-Ala2,N-methyl-Phe4,glyol5]enkephalin binding. High frequency trains of stimuli (10 Hz for 1 sec every 10 sec) were more effective than lower frequency stimulation (1 Hz continuous) at evoking opioid peptide release. Having identified an effective stimulation paradigm able to release endogenous opioids, the electrophysiological effects of endogenous opioids on CA3 pyramidal cells were measured in the guinea pig hippocampal slice preparation. Unlike exogenously applied opioids, stimulated release of endogenous opioid peptides from the perforant path did not significantly reduce inhibitory postsynaptic potential (IPSP) amplitudes recorded in CA3 pyramidal cells. However, perforant path stimulation in the presence of naloxone did cause a dramatic increase in IPSP amplitudes. CA3 pyramidal cells were not directly affected by perforant path stimulation. The naloxone-sensitive increase in IPSPs was delayed 3 min in onset and lasted for several minutes. In addition, the increase in the IPSPs was specifically blocked either by the beta adrenergic antagonist propranolol or by pretreating the animals with reserpine. These findings indicate that endogenous opioids regulate the effects of norepinephrine in the CA3 region of the guinea pig hippocampus. In addition, endogenously released norepinephrine appeared to act on GABAergic interneurons to increase the amplitude of the IPSP recorded in CA3 pyramidal cells.

Animals↗
PubMed1990

Chronic morphine exposure blocks opioid effects on both the early and late inhibitory postsynaptic potentials in hippocampal CA1 pyramidal cells.

The mu-opioid agonist, [N-MePhe3,D-Pro4]morphiceptin (PL017), significantly decreased the conductance changes measured during both the early and late inhibitory postsynaptic potentials (IPSP) in CA1 pyramidal cells. Although the conductance change during the early IPSP was much larger than that during the late IPSP, the relative decrease in conductance caused by 1 microM PL017 was similar for both. Chronic morphine treatment of rats prior to hippocampal slice preparation resulted in a loss of PL017 (1 microM) effects on both the early and late IPSPs. These results suggest that opioids have an equal ability to alter both early and late IPSPs in the CA1, that these effects are equally sensitive to chronic morphine, and that these measurements are a sensitive means of determining opioid tolerance in the hippocampus.

Animals↗
PubMed1990

Stimulation of endogenous opioid release displaces mu receptor binding in rat hippocampus.

Physiological release of endogenous opioids in the rat hippocampus was detected by an in vitro radioligand displacement assay using [3H][D-Ala2,N-methyl-Phe4,glyol5]enkephalin ([3H]DAGO), a mu selective opioid agonist. In this assay, radioligand binding to opioid receptors in the in vitro hippocampal slice was reduced by competition with endogenous opioids released following tissue depolarization. Veratridine-induced opioid release caused displacement of [3H]DAGO that could be blocked by either tetrodotoxin addition or calcium removal from the incubation buffer. Maximal displacement of [3H]DAGO also required the presence of peptidase inhibitors in the incubation buffer. None of the buffer composition changes directly affected [3H]DAGO binding to rat brain membranes. Calcium-dependent displacement of [3H]DAGO binding from mu receptor sites elicited by focal electrical stimulation depended on the intensity and frequency of stimulation and positioning of the electrode in the slice. Maximal displacement of [3H]DAGO binding was observed following high intensity (150-300 microA), high frequency (10-50 Hz) stimulation of the perforant path, a major afferent fiber system to the hippocampus previously shown to contain proenkephalin-derived opioids. Low frequency stimulation (0.1-1 Hz) was ineffective. Stimulation of the mossy fibers (containing both dynorphins and enkephalins) also significantly reduced mu receptor binding, but to a lesser extent. Electrical stimulation of the hippocampal slice at sites not containing opioid peptides did not cause mu receptor displacement. These results demonstrate that under physiological conditions, the release of endogenous opioids from the major opioid containing pathways can be detected in a single hippocampal slice following high frequency stimulation.

Animals↗
PubMed1990

Mu opioid receptor activation reduces inhibitory postsynaptic potentials in hippocampal CA3 pyramidal cells of rat and guinea pig.

Using intracellular recording techniques, we characterized synaptic responses of CA3 pyramidal cells to mu and kappa agonists in hippocampal slices from rats and guinea pigs. In rat CA3 pyramidal cells, the mu selective agonist (N-MePhe3,D-Pro4)-morphiceptin (PLO17) inhibited both the early and the late inhibitory postsynaptic potentials (IPSPs) and increased excitatory postsynaptic potential (EPSP) amplitudes. Voltage clamp analysis of synaptic currents indicated that the excitatory postsynaptic current were not increased by PLO17, showing that the apparent increase in EPSPs was a result of a decrease in the underlying IPSP. The kappa agonists trans-(+)-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide methanesulfonate and dynorphin A (1-17) had no effect on EPSPs or IPSP conductances measured in rat pyramidal cells. Maximal inhibition of IPSPs by PLO17 resulted in a bursting response to stimulation in rat but not guinea pig CA3 pyramidal cells. In guinea pig CA3 pyramidal cells, PLO17 also inhibited IPSP conductances but did not affect EPSP amplitudes. In contrast to the lack of effect in rat pyramidal cells, trans-(+)-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide methanesulfonate (100 nM) inhibited the late IPSP conductance without influencing the EPSP or the early IPSP conductance of guinea pig pyramidal cells. Dynorphin A (1-17) (0.01-10 microM) did not affect resting membrane properties or evoked synaptic conductances in either preparation. Mu receptor activationin the CA3 of rats and guinea pigs results in the inhibition of inhibitory synaptic input to pyramidal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

A novel interaction between dynorphin(1-13) and an N-methyl-D-aspartate site.

Dynorphin injected intrathecally in the rat results in a neurotoxicity behaviorally expressed as an irreversible loss of the thermally evoked tail-flick reflex. The excitatory amino acid antagonists DL-2-amino-5-phosphonovalerate (APV) and gamma-D-glutamylglycine (DGG) blocked the loss of the tail-flick reflex. The order of potency (APV greater than DGG) suggests that the N-methyl-D-aspartate (NMDA) subclass of excitatory amino acid receptors participate in the neurotoxicity. Additionally, intrathecal injection of APV results in a reversible loss of the tail-flick reflex, whereas with DGG doses which block the tail-flick reflex also result in hindlimb paralysis. These data suggest that neurotransmission in the tail-flick reflex pathway is, in part, mediated by NMDA receptors. From these and previous findings it was concluded that dynorphin neurotoxicity results from enhanced, excitotoxic, transmission across these synapses utilizing NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1988

Influence of dynorphin (1-13) on spinal reflexes in the rat.

Previously, we showed that intrathecal administration of dynorphin A (1-13) (dynorphin) in rats produced, within 5 min, a reversible inhibition of tail-shock vocalization, a reversible hind-limb paralysis and an irreversible loss of the tail-flick reflex. The selective loss of the tail-flick reflex was investigated using electrophysiologic methods and a dose of dynorphin effective in 90% of the rats. These studies revealed that intrathecal administration of dynorphin resulted in loss of the C-fiber initiated reflex when assayed 1 to 30 days after injection. On the other hand, reflexes initiated by Group I and III afferents were not obviously different from those seen in saline-injected animals. Application of dynorphin in situ on to the cord during stimulation of the dorsal root and recording of ventral root potentials demonstrated a rapid onset of peptide action. Initially the C-fiber evoked reflex was potentiated selectively with a decrease in conduction time. These responses were followed by inhibition of all reflexes for a short period of time after which the reflexes initiated by Group I and III afferents reappeared whereas the C-fiber reflex did not recover. This time course paralleled closely the time course of the loss of the tail-flick reflex suggesting that the two effects may be causally related. Furthermore, the selective N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonovalerate applied directly to the spinal cord during recording resulted in a reversible inhibition of the C-fiber-initiated reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1987

Intrathecal dynorphin(1-13) results in an irreversible loss of the tail-flick reflex in rats.

Intrathecal injection of dynorphin produced a loss of the tail-flick reflex that lasted throughout the 14-day experimental period whereas, the inclined plane test of motor function and tail-shock vocalization recovered within an hour. An important aspect of the loss of the tail-flick reflex was that it was an all-or-none event. At any dose of tail-flick latency either remained unchanged when compared with pre-injection latencies or the latency was elevated to the cut off time of 14 s. The ED50's +/- S.E.M. for tail-flick, inclined plane and tail-shock vocalization were 65.4 +/- 5.0, 67.7 +/- 5.0 and 68.0 +/- 3.9 nmol respectively. Results from the hot-plate test revealed no statistical difference between saline and dynorphin injected animals one day following the injection. Animals injected with morphine sulphate s.c. lost the tail-flick reflex but completely recovered by 24 h. Histology of the spinal cord of animals treated with dynorphin 24 h prior to sacrifice revealed dead neurons primarily in the ventral horn with little or no damage in the dorsal horn. These data demonstrate that dynorphin(1-13) injected intrathecally results in a rather specific neurotoxic action in the spinal cord.

Animals↗