Sensitization of Spinal Neurons by Non-Noxious Stimuli in the Awake but Not Anesthetized State

This essay looks at two papers published by Ed Perl and co-workers that identified specifically nociceptive neurons in the periphery and superficial dorsal horn. Bessou P and Perl ER. Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J Neurophysiol 32: 1025–1043 1969. Christensen BN and Perl ER. Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn. J Neurophysiol 33: 293–307 1970.

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A spinoparabrachial circuit defined by Tacr1 expression drives pain

eLife ◽

10.7554/elife.61135 ◽

2021 ◽

Vol 10 ◽

Author(s):

Arnab Barik ◽

Anupama Sathyamurthy ◽

James H Thompson ◽

Mathew Seltzer ◽

Ariel J Levine ◽

...

Keyword(s):

Spinal Cord ◽

Negative Emotions ◽

Parabrachial Nucleus ◽

Projection Neurons ◽

Spinal Neurons ◽

Lateral Parabrachial Nucleus ◽

Ongoing Pain ◽

And Behaviors ◽

Noxious Stimuli ◽

Pain Responses

Painful stimuli evoke a mixture of sensations, negative emotions and behaviors. These myriad effects are thought to be produced by parallel ascending circuits working in combination. Here we describe a pathway from spinal cord to brain for ongoing pain. Activation of a subset of spinal neurons expressing Tacr1 evokes a full repertoire of somatotopically-directed pain-related behaviors in the absence of noxious input. Tacr1 projection neurons (expressing NKR1) target a tiny cluster of neurons in the superior lateral parabrachial nucleus (PBN-SL). We showed that these neurons, which also express Tacr1 (PBN-SLTacr1), are responsive to sustained but not acute noxious stimuli. Activation of PBN-SLTacr1 neurons alone did not trigger pain responses but instead served to dramatically heighten nocifensive behaviors and suppress itch. Remarkably, mice with silenced PBN-SLTacr1 neurons ignored long-lasting noxious stimuli. Together, these data reveal new details about this spinoparabrachial pathway and its key role in the sensation of ongoing pain.

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Sensitization of Spinal Neurons by Non-noxious Stimuli in the Awake but Not Anesthetized State

Anesthesiology ◽

10.1097/00000542-199501000-00032 ◽

1995 ◽

Vol 82 (1) ◽

pp. 267-275 ◽

Cited By ~ 14

Author(s):

Juan F. Herrero ◽

Max P. Headley

Keyword(s):

Neuronal Excitability ◽

Dynamic Range ◽

Conscious State ◽

Spinal Neurons ◽

Mechanical Conditioning ◽

Sensory Pathways ◽

Before And After ◽

Nociceptive Afferents ◽

Peripheral Trauma ◽

Noxious Stimuli

Background The observation that peripheral trauma causes enhanced spinal neuronal excitability has provided the scientific rationale for the concept of "pre-emptive analgesia." The premise has been that only noxious stimuli cause sensitization in sensory pathways, but this premise has not been tested in the conscious state. Methods Responses of single spinal neurons were recorded in instrumented sheep that were untrained and free from drugs or recent surgery, in either fully conscious or halothane-anesthetized states. Receptive field (RF) size was measured before and after non-noxious mechanical conditioning stimulation. Results Noxious conditioning stimuli in anesthetized sheep caused enlargement of RF areas, as expected. Conditioning with nonpainful scratching or other stimuli was without effect in anesthetized animals; in marked contrast, it caused enlargement of RF size in conscious animals, in which 29 of 33 wide dynamic range units but only 1 of 12 low-threshold mechanoreceptive neurons were affected. Conclusions Sensitization of spinal sensory neurons evidently is a process that is not restricted to pathologic pain states but rather that occurs under normal physiologic conditions independent of painful stimuli. The significance of such sensitization processes therefore needs reevaluation. The sensitization triggered by non-nociceptive afferents is likely to be opioid-resistant and therefore may contribute to the rather disappointing results seen in several clinical trials of "pre-emptive analgesia."

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Spinal Cord Stimulation With “Conventional Clinical” and Higher Frequencies on Activity and Responses of Spinal Neurons to Noxious Stimuli: An Animal Study

Neuromodulation Technology at the Neural Interface ◽

10.1111/ner.12725 ◽

2017 ◽

Vol 21 (5) ◽

pp. 440-447 ◽

Cited By ~ 11

Author(s):

Shiying Li ◽

Jay P. Farber ◽

Bengt Linderoth ◽

Jiande Chen ◽

Robert D. Foreman

Keyword(s):

Spinal Cord ◽

Animal Study ◽

Spinal Cord Stimulation ◽

Spinal Neurons ◽

Noxious Stimuli

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A Single Cohort Study Collecting Interval Timed Incisional Epidermal and Dermal Tissue Samples During Surgical Procedures to Profile Temporal Response of Tissue After Noxious Stimuli

Case Medical Research ◽

10.31525/ct1-nct04224870 ◽

2020 ◽

Author(s):

Keyword(s):

Cohort Study ◽

Surgical Procedures ◽

Temporal Response ◽

Tissue Samples ◽

Dermal Tissue ◽

Noxious Stimuli ◽

Single Cohort

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Faculty Opinions recommendation of Ethnic differences in cardiovascular-somatosensory interactions and in the central processing of noxious stimuli.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12491956.13711054 ◽

2011 ◽

Author(s):

Claudia Campbell

Keyword(s):

Ethnic Differences ◽

Central Processing ◽

Noxious Stimuli

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Developmental-Dependent Action of Microtubule Depolymerization on the Function and Structure of Synaptic Glycine Receptor Clusters in Spinal Neurons

Journal of Neurophysiology ◽

10.1152/jn.00364.2003 ◽

2004 ◽

Vol 91 (2) ◽

pp. 1036-1049 ◽

Cited By ~ 27

Author(s):

Brigitte van Zundert ◽

Francisco J. Alvarez ◽

Juan Carlos Tapia ◽

Hermes H. Yeh ◽

Emilio Diaz ◽

...

Keyword(s):

Average Length ◽

Glycine Receptor ◽

Colchicine Treatment ◽

Morphological Properties ◽

Microtubule Depolymerization ◽

Spinal Neurons ◽

Functional Changes ◽

Microtubule Disruption ◽

Immature Neurons ◽

Mature Neurons

Microtubules have been proposed to interact with gephyrin/glycine receptors (GlyRs) in synaptic aggregates. However, the consequence of microtubule disruption on the structure of postsynaptic GlyR/gephyrin clusters is controversial and possible alterations in function are largely unknown. In this study, we have examined the physiological and morphological properties of GlyR/gephyrin clusters after colchicine treatment in cultured spinal neurons during development. In immature neurons (5-7 DIV), disruption of microtubules resulted in a 33 ± 4% decrease in the peak amplitude and a 72 ± 15% reduction in the frequency of spontaneous glycinergic miniature postsynaptic currents (mIPSCs) recorded in whole cell mode. However, similar colchicine treatments resulted in smaller effects on 10-12 DIV neurons and no effect on mature neurons (15-17 DIV). The decrease in glycinergic mIPSC amplitude and frequency reflects postsynaptic actions of colchicine, since postsynaptic stabilization of microtubules with GTP prevented both actions and similar reductions in mIPSC frequency were obtained by modifying the Cl- driving force to obtain parallel reductions in mIPSC amplitude. Confocal microscopy revealed that colchicine reduced the average length and immunofluorescence intensity of synaptic gephyrin/GlyR clusters in immature (approximately 30%) and intermediate (approximately 15%) neurons, but not in mature clusters. Thus the structural and functional changes of postsynaptic gephyrin/GlyR clusters after colchicine treatment were tightly correlated. Finally, RT-PCR, kinetic analysis and picrotoxin blockade of glycinergic mIPSCs indicated a reorganization of the postsynaptic region from containing both α2β and α1β GlyRs in immature neurons to only α1β GlyRs in mature neurons. Microtubule disruption preferentially affected postsynaptic sites containing α2β-containing synaptic receptors.

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