scholarly journals Calcium Channel Subtypes in Lamprey Sensory and Motor Neurons

1997 ◽  
Vol 78 (3) ◽  
pp. 1334-1340 ◽  
Author(s):  
A. El Manira ◽  
N. Bussières
Keyword(s):  
Spinal Cord ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Sensory Neurons ◽  
Motor Neurons ◽  
Calcium Channel Antagonist ◽  
Calcium Currents ◽  
Spinal Cord Neurons ◽  
Channel Current ◽  
Dorsal Cells

El Manira, A. and N. Bussières. Calcium channel subtypes in lamprey sensory and motor neurons. J. Neurophysiol. 78: 1334–1340, 1997. Pharmacologically distinct calcium channels have been characterized in dissociated cutaneous sensory neurons and motoneurons of the larval lamprey spinal cord. To enable cell identification, sensory dorsal cells and motoneurons were selectively labeled with fluorescein-coupled dextran amine in the intact spinal cord in vitro before dissociation. Calcium channels present in sensory dorsal cells, motoneurons, and other spinal cord neurons were characterized with the use of whole cell voltage-clamp recordings and specific calcium channel agonist and antagonists. The results show that a transient low-voltage-activated (LVA) calcium current was present in a proportion of sensory dorsal cells but not in motoneurons, whereas high-voltage-activated (HVA) calcium currents were seen in all neurons recorded. The different components of HVA current were dissected pharmacologically and similar results were obtained for both dorsal cells and motoneurons. The N-type calcium channel antagonist ω-conotoxin-GVIA(ω-CgTx) blocked >70% of the HVA current. A large part of the ω-CgTx block was reversed after washout of the toxin. The L-type calcium channel antagonist nimodipine blocked ∼15% of the total HVA current. The dihydropyridine agonist (±)-BayK 8644 markedly increased the amplitude of the calcium channel current. The BayK-potentiated current was not affected by ω-CgTx, indicating that the reversibility of the ω-CgTx effect is not due to a blockade of L-type channels. Simultaneous application of ω-CgTx and nimodipine left ∼15% of the HVA calcium channel current, a small part of which was blocked by the P/Q-type channel antagonist ω-agatoxin-IVA. In the presence of the three antagonists, the persistent residual current (∼10%) was completely blocked by cadmium. Our results provide evidence for the existence of HVA calcium channels of the N, L, and P/Q types and other HVA calcium channels in lamprey sensory neurons and motoneurons. In addition, certain types of neurons express LVA calcium channels.

Effects of ω-Agatoxin IVA, a P-Type Calcium Channel Antagonist, on the Development of Spinal Neuronal Hyperexcitability Caused by Knee Inflammation in Rats

1999 ◽  
Vol 81 (6) ◽  
pp. 2620-2626 ◽  
Author(s):  
Johannes Nebe ◽  
Andrea Ebersberger ◽  
Horacio Vanegas ◽  
Hans-Georg Schaible
Keyword(s):  
Spinal Cord ◽  
Knee Joint ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Calcium Channel Antagonist ◽  
Dynamic Range ◽  
Control Group ◽  
Spinal Cord Neurons ◽  
Neuronal Hyperexcitability ◽  
P Type

Effects of ω-agatoxin IVA, a P-type calcium channel antagonist, on the development of spinal neuronal hyperexcitability caused by knee inflammation in rats. Both N- and P-type high-threshold calcium channels are located presynaptically in the CNS and are involved in the release of transmitters. To investigate the importance of P-type calcium channels in the generation of inflammation-evoked hyperexcitability of spinal cord neurons, electrophysiological recordings were made from wide-dynamic-range neurons with input from the knee joint in the anesthetized rat. The responses of each neuron to innocuous and noxious pressure onto the knee and the ankle were continuously assessed before and during the development of an inflammation in the knee joint induced by the injections of K/C into the joint cavity. The specific antagonist at P-type calcium channels ω-agatoxin was administered into a 30-μl trough on the spinal cord surface above the recorded neuron. In most neurons the application of ω-agatoxin before induction of inflammation slightly enhanced the responses to pressure onto the knee and ankle or left them unchanged. Two different protocols were then followed. In the control group (13 rats) only Tyrode was administered to the spinal cord during and after induction of inflammation. In these neurons the responses to mechanical stimuli applied to both the inflamed knee and to the noninflamed ankle showed a significant increase over 4 h. In the experimental group (12 rats) ω-agatoxin was applied during knee injection and in five 15-min periods up to 180 min after kaolin. This prevented the increase of the neuronal responses to innocuous pressure onto the knee and to innocuous and noxious pressure onto the ankle; only the responses to noxious pressure onto the knee were significantly enhanced during development of inflammation. Thus the development of inflammation-evoked hyperexcitability was attenuated by ω-agatoxin, and this suggests that P-type calcium channels in the spinal cord are involved in the generation of inflammation-evoked hyperexcitability of spinal cord neurons. Finally, when ω-agatoxin was administered to the spinal cord 4 h after the kaolin injection, i.e., when inflammation-evoked hyperexcitability was fully established, the responses to innocuous and noxious pressure onto the knee were reduced by 20–30% on average. The shift in the effect of ω-agatoxin, from slight facilitation or no change of the responses before inflammation to inhibition in the state of hyperexcitability, indicates that P-type calcium channels are important for excitatory synaptic transmission involved in the maintenance of inflammation-evoked hyperexcitability.

scholarly journals Inhibition of L-type calcium-channel activity by thapsigargin and 2,5-t-butylhydroquinone, but not by cyclopiazonic acid

1994 ◽  
Vol 302 (1) ◽  
pp. 147-154 ◽  
Author(s):  
E J Nelson ◽  
C C R Li ◽  
R Bangalore ◽  
T Benson ◽  
R S Kass ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Cyclopiazonic Acid ◽  
Calcium Currents ◽  
Pituitary Cells ◽  
Channel Activity ◽  
Patch Clamp Technique ◽  
Channel Current ◽  
Low Concentrations ◽  
Ic50 Values

Thapsigargin (TG), 2,5-t-butylhydroquinone (tBHQ) and cyclopiazonic acid (CPA) all inhibit the initial Ca(2+)-response to thyrotropin-releasing hormone (TRH) by depleting intracellular Ca2+ pools sensitive to inositol 1,4,5-trisphosphate (IP3). Treatment of GH3 pituitary cells for 30 min with 5 nM TG, 500 nM tBHQ or 50 nM CPA completely eliminated the TRH-induced spike in intracellular free Ca2+ ([Ca2+]i). Higher concentrations of TG and tBHQ, but not CPA, were also found to inhibit strongly the activity of L-type calcium channels, as measured by the increase in [Ca2+]i or 45Ca2+ influx stimulated by depolarization. TG and tBHQ blocked high-K(+)-stimulated 45Ca2+ uptake, with IC50 values of 10 and 1 microM respectively. Maximal inhibition of L-channel activity was achieved 15-30 min after drug addition. Inhibition by tBHQ was reversible, whereas inhibition by TG was not. TG and CPA did not affect spontaneous [Ca2+]i oscillations when tested at concentrations adequate to deplete the IP3-sensitive Ca2+ pool. However, 20 microM TG and 10 microM tBHQ blocked [Ca2+]i oscillations completely. The effect of drugs on calcium currents was measured directly by using the patch-clamp technique. When added to the external bath, 10 microM CPA caused a sustained increase in the calcium-channel current amplitude over 8 min, 10 microM tBHQ caused a progressive inhibition, and 10 microM TG caused an enhancement followed by a sustained block of the calcium current over 8 min. In summary, CPA depletes IP3-sensitive Ca2+ stores and does not inhibit voltage-operated calcium channels. At sufficiently low concentrations, TG depletes IP3-sensitive stores without inhibiting L-channel activity, but, for tBHQ, inhibition of calcium channels occurs at concentrations close to those needed to block agonist mobilization of intracellular Ca2+.

scholarly journals Anti–PD-1 treatment impairs opioid antinociception in rodents and nonhuman primates

2020 ◽  
Vol 12 (531) ◽  
pp. eaaw6471 ◽  
Author(s):  
Zilong Wang ◽  
Changyu Jiang ◽  
Qianru He ◽  
Megumi Matsuda ◽  
Qingjian Han ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Cancer Pain ◽  
Opioid Receptor ◽  
Sensory Neurons ◽  
Nonhuman Primates ◽  
Intrathecal Injection ◽  
Long Term Potentiation ◽  
Calcium Currents ◽  
Spinal Cord Neurons ◽  
Nociceptive Neurons

Emerging immunotherapies with monoclonal antibodies against programmed cell death protein–1 (PD-1) have shown success in treating cancers. However, PD-1 signaling in neurons is largely unknown. We recently reported that dorsal root ganglion (DRG) primary sensory neurons express PD-1 and activation of PD-1 inhibits neuronal excitability and pain. Opioids are mainstay treatments for cancer pain, and morphine produces antinociception via mu opioid receptor (MOR). Here, we report that morphine antinociception and MOR signaling require neuronal PD-1. Morphine-induced antinociception after systemic or intrathecal injection was compromised in Pd1−/− mice. Morphine antinociception was also diminished in wild-type mice after intravenous or intrathecal administration of nivolumab, a clinically used anti–PD-1 monoclonal antibody. In mouse models of inflammatory, neuropathic, and cancer pain, spinal morphine antinociception was compromised in Pd1−/− mice. MOR and PD-1 are coexpressed in sensory neurons and their axons in mouse and human DRG tissues. Morphine produced antinociception by (i) suppressing calcium currents in DRG neurons, (ii) suppressing excitatory synaptic transmission, and (iii) inducing outward currents in spinal cord neurons; all of these actions were impaired by PD-1 blockade in mice. Loss of PD-1 also enhanced opioid-induced hyperalgesia and tolerance and potentiates opioid-induced microgliosis and long-term potentiation in the spinal cord in mice. Last, intrathecal infusion of nivolumab inhibited intrathecal morphine-induced antinociception in nonhuman primates. Our findings demonstrate that PD-1 regulates opioid receptor signaling in nociceptive neurons, leading to altered opioid-induced antinociception in rodents and nonhuman primates.

Modulation of calcium currents and membrane properties by substance P in the lamprey spinal cord

2013 ◽  
Vol 110 (2) ◽  
pp. 286-296 ◽  
Author(s):  
Carolina Thörn Pérez ◽  
Russell H. Hill ◽  
Sten Grillner
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Input Resistance ◽  
Reciprocal Inhibition ◽  
Calcium Currents ◽  
Membrane Properties ◽  
Fictive Locomotion ◽  
Burst Frequency

Substance P is endogenously released within the locomotor network of the adult lamprey, accelerates the burst frequency of fictive locomotion, and reduces the reciprocal inhibition. Previous studies have shown that dopamine, serotonin, and GABA regulate calcium channels, which control neurotransmitter release, action potential duration, and slow afterhyperpolarization (sAHP). Here we examine the effect of substance P on calcium channels in motoneurons and commissural interneurons using whole cell patch clamp in the lamprey spinal cord. This study analyzed the effects of substance P on calcium currents activated in voltage clamp. We examined the calcium-dependent sAHP in current clamp, to determine the involvement of three calcium channel subtypes modulated by substance P. The effects of substance P on membrane potential and during N-methyl-d-aspartic acid (NMDA) induced oscillations were also analyzed. Depolarizing voltage steps induced inward calcium currents. Substance P reduced the currents carried by calcium by 61% in commissural interneurons and by 31% in motoneurons. Using specific calcium channel antagonists, we show that substance P reduces the sAHP primarily by inhibiting N-type (CaV2.2) channels. Substance P depolarized both motoneurons and commissural interneurons, and we present evidence that this occurs due to an increased input resistance. We also explored the effects of substance P on NMDA-induced oscillations in tetrodotoxin and found it caused a frequency increase. Thus the reduction of calcium entry by substance P and the accompanying decrease of the sAHP amplitude, combined with substance P potentiation of currents activated by NMDA, may both contribute to the increase in fictive locomotion frequency.

Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint

1996 ◽  
Vol 76 (6) ◽  
pp. 3740-3749 ◽  
Author(s):  
V. Neugebauer ◽  
H. Vanegas ◽  
J. Nebe ◽  
P. Rumenapp ◽  
H. G. Schaible
Keyword(s):  
Spinal Cord ◽  
Knee Joint ◽  
Calcium Channels ◽  
Mechanical Stimulation ◽  
Topical Administration ◽  
Knee Joints ◽  
Spinal Cord Neurons ◽  
Inflammatory Conditions ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

1. The present study addresses the involvement of voltage-dependent calcium channels of the N and L type in the spinal processing of innocuous and noxious input from the knee joint, both under normal conditions and under inflammatory conditions in which spinal cord neurons become hyperexcitable. In 30 anesthetized rats, extracellular recordings were performed from single dorsal horn neurons in segments 1–4 of the lumbar spinal cord. All neurons had receptive fields in the ipsilateral knee joint. In 22 rats, an inflammation was induced in the ipsilateral knee joint by kaolin and carrageenan 4–16 h before the recordings. The antagonist at N-type calcium channels, omega-conotoxin GVIA (omega-CTx GVIA), was administered topically in solution to the dorsal surface of the spinal cord at the appropriate spinal segments in 6 rats with normal joints and in 12 rats with inflamed knee joints. The antagonist at L-type channels, nimodipine, was administered topically in 5 rats with normal joints and in 11 rats with inflamed knee joints. In another five rats with inflamed joints, antagonists at L-type calcium channels (diltiazem and nimodipine) and omega-CTx GVIA were administered ionophoretically with multibarrel electrodes close to the neurons recorded. 2. The topical administration of omega-CTx GVIA to the spinal cord reduced the responses to both innocuous and noxious pressure applied to the knee joint in a sample of 11 neurons with input from the normal joint and in a sample of 16 neurons with input from the inflamed joint (hyperexcitable neurons). The responses were decreased to approximately 65% of the predrug values within administration times of 30 min. A similar reduction of the responses to innocuous and noxious pressure was observed when omega-CTx GVIA was administered ionophoretically to nine hyperexcitable neurons. In neurons with input from the normal or the inflamed knee joint, the administration of omega-CTx GVIA led also to a reduction of the responses to innocuous and noxious pressure applied to the noninflamed ankle joint. 3. The topical administration of nimodipine decreased the responses to innocuous and noxious pressure applied to the knee in a sample of 9 neurons with input from the normal joint and in a sample of 16 neurons with input from the inflamed knee joint (hyperexcitable neurons). Within administration times of 30 min, the responses were reduced to approximately 70% of the predrug values. In hyperexcitable neurons, the responses to innocuous and noxious pressure applied to the knee were also decreased during ionophoretic administration of nimodipine (6 neurons) and diltiazem (9 neurons). When the noninflamed ankle was stimulated, the responses to innocuous pressure were reduced neither in neurons with input from the normal knee nor in neurons with input from the inflamed knee, but the responses of hyperexcitable neurons to noxious pressure onto the ankle were reduced. The ionophoretic administration of the agonist at the L-type calcium channel, S(-)-Bay K 8644, enhanced the responses to mechanical stimulation of the knee joint in all 14 hyperexcitable neurons tested. The effect of S(-)-Bay K 8644 was counteracted by both diltiazem (in 6 of 6 neurons) and nimodipine (in 5 of 5 neurons). 4. These data show that antagonists at both the N- and the L-type voltage-dependent calcium channels influence the spinal processing of input from the knee joint. The data suggest, therefore, that voltage-dependent calcium calcium channels of both the N and the L type are important for the sensory functions of the spinal cord. They are involved in the spinal processing of nonnociceptive as well as nociceptive mechanosensory input from the joint, both under normal and inflammatory conditions. The present results show in particular that N- and L-type channels are likely to be involved in the generation of pain evoked by noxious mechanical stimulation in normal tissue as well as in the mechanical hyperalgesia that is usually pres

Experimental Spinal Cord Injury: Effect of a Calcium Channel Antagonist (Nicardipine)

Neurosurgery ◽  
1988 ◽  
Vol 22 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Perry Black ◽  
Ronald S. Markowitz ◽  
Sydney D. Finkelstein ◽  
Kathleen McMonagle-Strucko ◽  
John A. Gillespie
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Calcium Channel ◽  
Calcium Channel Antagonist ◽  
Experimental Spinal Cord Injury ◽  
Cord Injury

Evaluation of the calcium channel antagonist nimodipine after experimental spinal cord injury

1993 ◽  
Vol 39 (5) ◽  
pp. 403-408 ◽  
Author(s):  
Siavash S. Haghighi ◽  
Tyler Stiens ◽  
John J. Oro ◽  
Richard Madsen
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Calcium Channel ◽  
Calcium Channel Antagonist ◽  
Experimental Spinal Cord Injury ◽  
Cord Injury

Effect of Cortical Spreading Depression on Activity of Trigeminovascular Sensory Neurons

Cephalalgia ◽  
1999 ◽  
Vol 19 (7) ◽  
pp. 631-638 ◽  
Author(s):  
GA Lambert ◽  
J Michalicek ◽  
RJ Storer ◽  
AS Zagami
Keyword(s):  
Spinal Cord ◽  
Sensory Neurons ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Cervical Spinal Cord ◽  
Discharge Rate ◽  
Evoked Responses ◽  
Spinal Cord Neurons ◽  
Sagittal Sinus ◽  
Upper Cervical

The effect of cortical spreading depression, a proposed initiating event for migraine pain, on cortical blood flow (laser Doppler method) and on the spontaneous firing rate and stimulus-evoked responses of trigemino-cervical neurons with craniovascular input was studied in 17 neurons in 8 cats anesthetized with chloralose. Cortical spreading depression, induced via cortical pinprick injury, produced an initial wave of cortical hyperemia (243 ± 57% of control) and a later and smaller phase of oligemia (96 ± 4% of control). Neither the basal discharge rate (6.7 ± 1.7 sec-1) nor the evoked responses to electrical stimulation of the superior sagittal sinus (4.1 ± 0.8 discharges per stimulus) of upper cervical spinal cord neurons was altered over periods of up to 2 h following one, two, or three waves of spreading cortical depression. We conclude that a small number of episodes of cortical spreading depression is not capable of activating C2 cervical spinal cord craniovascular sensory neurons in the cat.

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