Descending Control of Spinal Cord Nociceptive Neurons

Central sensitization, a prolonged hyperexcitability of dorsal horn nociceptive neurons, is a major contributor to abnormal pain processing after spinal cord injury (SCI). Dendritic spines are micron-sized dendrite protrusions that can regulate the efficacy of synaptic transmission. Here we used a computational approach to study whether changes in dendritic spine shape, density, and distribution can individually, or in combination, adversely modify the input–output function of a postsynaptic neuron to create a hyperexcitable neuronal state. The results demonstrate that a conversion from thin-shaped to more mature, mushroom-shaped spine structures results in enhanced synaptic transmission and fidelity, improved frequency-following ability, and reduced inhibitory gating effectiveness. Increasing the density and redistributing spines toward the soma results in a greater probability of action potential activation. Our results demonstrate that changes in dendritic spine morphology, documented in previous studies on spinal cord injury, contribute to the generation of pain following SCI.

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Descending Control of Turning Locomotor Activity in Larval Lamprey: Neurophysiology and Computer Modeling

Journal of Neurophysiology ◽

10.1152/jn.1997.78.1.214 ◽

1997 ◽

Vol 78 (1) ◽

pp. 214-228 ◽

Cited By ~ 35

Author(s):

Andrew D. McClellan ◽

André Hagevik

Keyword(s):

Spinal Cord ◽

Locomotor Activity ◽

Brain Stem ◽

Computer Modeling ◽

Cycle Time ◽

Excitatory Input ◽

Burst Activity ◽

Descending Input ◽

The Right ◽

Descending Control

McClellan, Andrew D. and André Hagevik. Descending control of turning locomotor activity in larval lamprey: neurophysiology and computer modeling. J. Neurophysiol. 78: 214–228, 1997. The purpose of the present study was to examine the mechanisms that produce natural spontaneous turning maneuvers in larval lamprey. During swimming, spontaneous turning movements began with a larger-than-normal bending of the head to one side. Subsequently, undulations propagated down the body with greater amplitude on the side ipsilateral to the turn. During turning to one side, which usually occurred within one cycle, the amplitude and duration of ipsilateral muscle burst activity as well as overall cycle time increased significantly with increasing turn angle. In in vitro brain/spinal cord preparations, brief electrical stimulation applied to the left side of the oral hood at the onset of locomotor burst activity on the right side of the spinal cord produced turninglike motor activity. During the perturbed cycle, the duration and amplitude of the burst on the right as well as cycle time were significantly larger than during preceding control cycles. In several lower vertebrates, unilateral stimulation in brain stem locomotor regions elicits asymmetric, turninglike locomotor activity. In the lamprey, unilateral chemical microstimulation in brain stem locomotor regions elicited continuous asymmetric locomotor activity, but there was little change in cycle time, as occurs during the single turning cycles in whole animals. The descending mechanisms responsible for producing turning locomotor activity were examined with the use of a computer model consisting of left and right phase oscillators in the spinal cord that were coupled by net reciprocal inhibition. With relatively weak reciprocal coupling, a brief unilateral descending excitatory input to one oscillator produced effects ipsilaterally, but there was little effect on the contralateral oscillator. Turninglike patterns could be produced by each of the following modifications of the model: 1) unilateral descending input and relatively strong reciprocal coupling; 2) unilateral descending input that phase shifted as well as increased the amplitude of the waveform generated by an oscillator on one side; and 3) brief descending modulatory inputs that excited the oscillator on one side and inhibited the contralateral oscillator. In all three cases, there was an increase in “burst” duration ipsilateral to the excitatory input and an increase in cycle time, similar to turning locomotor activity in whole animals. It is likely that turning maneuvers are mediated by descending modulatory inputs primarily to the spinal oscillator networks, which control the timing of burst activity, but perhaps also to motoneurons for axial musculature.

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Enkephalin-immunoreactive nociceptive neurons in the cat spinal cord

Neuroreport ◽

10.1097/00001756-199201000-00006 ◽

1992 ◽

Vol 3 (1) ◽

pp. 25-28 ◽

Cited By ~ 21

Author(s):

A. Ribeiro-da-Silva ◽

Y. De Koninck ◽

A. C. Cuello ◽

J. L. Henry

Keyword(s):

Spinal Cord ◽

Nociceptive Neurons

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Effect of different concentrations of iontophoretic nociceptin on distinct classes of nociceptive neurons in rat spinal cord

Brain Research ◽

10.1016/s0006-8993(01)02155-2 ◽

2001 ◽

Vol 897 (1-2) ◽

pp. 184-187 ◽

Cited By ~ 5

Author(s):

Maria Luisa Sotgiu ◽

Paola Bellomi ◽

Gabriele Biella

Keyword(s):

Spinal Cord ◽

Rat Spinal Cord ◽

Nociceptive Neurons

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Elevated Expression and Activity of Sodium Leak Channel Contributes to Neuronal Sensitization of Inflammatory Pain in Rats

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.723395 ◽

2021 ◽

Vol 14 ◽

Author(s):

Jia Li ◽

Yali Chen ◽

Jin Liu ◽

Donghang Zhang ◽

Peng Liang ◽

...

Keyword(s):

Spinal Cord ◽

Inflammatory Pain ◽

Neuronal Excitability ◽

Clinical Symptoms ◽

Thermal Sensation ◽

Spontaneous Pain ◽

Nociceptive Neurons ◽

Leak Channel ◽

Spinal Dorsal ◽

Expression And Activity

Inflammatory pain encompasses many clinical symptoms, and there is no satisfactory therapeutic target. Neuronal hyperexcitability and/or sensitization of the primary nociceptive neurons in the dorsal root ganglion (DRG) and spinal dorsal horn are critical to the development and maintenance of inflammatory pain. The sodium leak channel (NALCN), a non-selective cation channel, mediates the background Na+ leak conductance and controls neuronal excitability. It is unknown whether abnormal activity of NALCN mediates the pathological process of inflammatory pain. Complete Freund’s adjuvant (CFA) was injected into the left footpad of rats to induce inflammatory pain. The thresholds of mechanical and thermal sensation and spontaneous pain behaviors were assessed. The expression of NALCN in DRG and spinal dorsal cord was measured. NALCN currents and the contribution of NALCN to neuronal excitability in the DRG and spinal dorsal cord were recorded using whole-cell patch-clamping recording. NALCN was abundantly expressed in neurons of the DRG and spinal dorsal cord. In acutely isolated DRG neurons and spinal cord slices from rats with CFA-induced inflammatory pain, NALCN currents and neuronal excitability were increased. Subsequently, intrathecal and sciatic nerve injection of NALCN-small interfering RNA (siRNA) decreased NALCN mRNA and reverted NALCN currents to normal levels, and then reduced CFA-induced neuronal excitability and alleviated pain symptoms. Furthermore, pain-related symptoms were significantly prevented by the NALCN-shRNA-mediated NALCN knockdown in DRG and spinal cord. Therefore, increased expression and activity of NALCN contributed to neuronal sensitization in CFA-induced inflammatory pain. NALCN may be a novel molecular target for the control of inflammatory pain.

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The importance of descending modulatory pain systems

10.1093/med/9780198834359.003.0044 ◽

2018 ◽

Author(s):

Enrique Collantes

Keyword(s):

Spinal Cord ◽

Nervous System ◽

Peripheral Nervous System ◽

Dorsal Horn ◽

Neural System ◽

Complex Interaction ◽

Descending Pathways ◽

Cerebral Structures ◽

Descending Control

The landmark paper discussed in this chapter is ‘Descending control of pain’, published by M. J. Millan in 2002. The perception of pain is affected by a complex interaction between nociceptors in the dorsal horn of the spinal cord, systems that transfer messages to cerebral structures. The complex interaction between the CNS and the peripheral nervous system in a modifiable and plastic neural system makes the perception of pain unique for each individual. In this regard, the author outlines the neurobiology of pain, providing a detailed description of the descending pathways which modulate the activity of spinal nociceptors which are located in the dorsal horn and which transfer nociceptive messages to cerebellar structures.

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

Science Translational Medicine ◽

10.1126/scitranslmed.aaw6471 ◽

2020 ◽

Vol 12 (531) ◽

pp. eaaw6471 ◽

Cited By ~ 8

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.

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Intrathecal Grafting of Porcine Chromaffin Cells Reduces Formalin-Evoked c-Fos Expression in the Rat Spinal Cord

Cell Transplantation ◽

10.3727/000000005783982963 ◽

2005 ◽

Vol 14 (6) ◽

pp. 353-365 ◽

Cited By ~ 12

Author(s):

J. C. Sol ◽

R. Y. Li ◽

B. Sallerin ◽

S. Jozan ◽

H. Zhou ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Chromaffin Cells ◽

Formalin Injection ◽

Adrenal Chromaffin Cells ◽

Nociceptive Neurons ◽

Analgesic Effects ◽

Bovine Chromaffin Cells ◽

Fos Expression ◽

Adrenal Chromaffin

Chromaffin cells from the adrenal gland secrete a combination of neuroactive compounds including catecholamines, opioid peptides, and growth factors that have strong analgesic effects, especially when administered intrathecally. Preclinical studies of intrathecal implantation with xenogeneic bovine chromaffin cells in rats have provided conflicting data with regard to analgesic effects, and recent concern over risk of prion transmission has precluded their use in human clinical trials. We previously developed a new, safer source of adult adrenal chromaffin cells of porcine origin and demonstrated an in vivo antinociceptive effect in the formalin test, a rodent model of tonic pain. The goal of the present study was to confirm porcine chromaffin cell analgesic effects at the molecular level by evaluating neural activity as reflected by spinal cord c-Fos protein expression. To this end, the expression of c-Fos in response to intraplantar formalin injection was evaluated in animals following intrathecal grafting of 106 porcine or bovine chromaffin cells. For the two species, adrenal chromaffin cells significantly reduced the tonic phases of the formalin response. Similarly, c-Fos-like immunoreactive neurons were markedly reduced in the dorsal horns of animals that had received injections of xenogeneic chromaffin cells. This reduction was observed in both the superficial (I—II) and deep (V—VI) lamina of the dorsal horn. The present study demonstrates that both xenogeneic porcine and bovine chromaffin cells transplanted into the spinal subarachnoid space of the rat can suppress formalin-evoked c-Fos expression equally, in parallel with suppression of nociceptive behaviors in the tonic phase of the test. These findings confirm previous reports that adrenal chromaffin cells may produce antinociception by inhibiting activation of nociceptive neurons in the spinal dorsal horn. Taken together these results support the concept that porcine chromaffin cells may offer an alternative xenogeneic cell source for transplants delivering pain-reducing neuroactive substances.

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