Morphological and functional properties distinguish the substance P and gastrin-releasing peptide subsets of excitatory interneuron in the spinal cord dorsal horn

Dickie, Allen C.; Bell, Alasdair F.; Iwagaki, Noboru; Polgár, Erika; Gutièrrez‐Mecinas, María; Kelly, Rosalind; Lyon, Heather; Turnbull, Kirsten; West, Steven J.; Etlin, Alexander; Bráz, Joao; Watanabe, Masahiko; Bennett, David L.H.; Basbaum, Allan I.; Riddell, John S.; Todd, Andrew J.

doi:10.1097/j.pain.0000000000001406

Cited by 66 publications

(148 citation statements)

References 75 publications

(161 reference statements)

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“…The mouse monoclonal antibody NeuN, which was generated against cell nuclei extracted from mouse brain, was found to react with a protein specific to neurons (Mullen, Buck, & Smith, ), and this has subsequently been identified as the splicing factor Fox‐3 (Kim, Adelstein, & Kawamoto, ). We have found that the guinea‐pig NeuN antibody stains the same cells as the mouse antibody (Dickie et al, ). Staining with the neurotensin antibody is identical to that seen with a well‐characterized rabbit neurotensin antibody, and is blocked by preincubation with 10 −4 M neurotensin (Porteous et al, ).…”

Section: Methodsmentioning

confidence: 79%

“…Häring et al did not define a population specifically associated with GRP expression, and they reported that GRP mRNA was present in cells belonging to several of their populations (Glut5‐12). Although virtually all eGFP‐expressing cells in the GRP‐eGFP mouse contain GRP mRNA, many cells with GRP mRNA do not express GFP in this line (Dickie et al, ; Solorzano et al, ), and this suggests that eGFP is restricted to a subset of the GRP‐expressing cells. We have found that at least some of these GRP‐eGFP cells contain mRNA for the neuromedin U receptor 2 (Nmur2; AMB, unpublished data), and these may therefore correspond to the Glut8 population, in which Nmur2 mRNA is enriched.…”

Section: Discussionmentioning

confidence: 99%

“…We did see a moderate degree of overlap between Tac1 and CCK, with around a quarter of CCK+ cells in laminae I‐II being Tac1‐positive. However, these only accounted for 3% of Tac1 cells, indicating that CCK is seldom, if ever, expressed by substance P radial cells in lamina II (Dickie et al, ). The cells that express both CCK and Tac1 in this region could belong to either Glut9 or Glut10, because both peptides are significantly expressed in these clusters, and they include cells in the superficial dorsal horn.…”

Section: Discussionmentioning

confidence: 99%

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Expression of cholecystokinin by neurons in mouse spinal dorsal horn

Gutièrrez‐Mecinas

Bell

Shepherd

et al. 2019

J of Comparative Neurology

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Excitatory interneurons account for the majority of dorsal horn neurons, and are required for perception of normal and pathological pain. We have identified largely non‐overlapping populations in laminae I‐III, based on expression of substance P, gastrin‐releasing peptide, neurokinin B, and neurotensin. Cholecystokinin (CCK) is expressed by many dorsal horn neurons, particularly in the deeper laminae. Here, we have used immunocytochemistry and in situ hybridization to characterize the CCK cells. We show that they account for ~7% of excitatory neurons in laminae I‐II, but between a third and a quarter of those in lamina III. They are largely separate from the neurokinin B, neurotensin, and gastrin‐releasing peptide populations, but show limited overlap with the substance P cells. Laminae II‐III neurons with protein kinase Cγ (PKCγ) have been implicated in mechanical allodynia following nerve injury, and we found that around 50% of CCK cells were PKCγ‐immunoreactive. Neurotensin is also expressed by PKCγ cells, and among neurons with moderate to high levels of PKCγ, ~85% expressed CCK or neurotensin. A recent transcriptomic study identified mRNA for thyrotropin‐releasing hormone in a specific subpopulation of CCK neurons, and we show that these account for half of the CCK/PKCγ cells. These findings indicate that the CCK cells are distinct from other excitatory interneuron populations that we have defined. They also show that PKCγ cells can be assigned to different classes based on neuropeptide expression, and it will be important to determine the differential contribution of these classes to neuropathic allodynia.

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Section: Methodsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Expression of cholecystokinin by neurons in mouse spinal dorsal horn

Gutièrrez‐Mecinas

Bell

Shepherd

et al. 2019

J of Comparative Neurology

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“…Recent work suggests that in neurons expressing gastrin‐releasing peptide, the single‐spiking phenotype is seen in a third of cells (Dickie et al. ); it is possible that neurons expressing this peptide more sparse or absent in the TNc.…”

Section: Discussionmentioning

confidence: 99%

“…Instead, our data indicate that single-spiking neurons are much less frequent in the mouse TNc at age p14-35 and recorded at 28°C than in the dorsal horn preparation. Recent work suggests that in neurons expressing gastrin-releasing peptide, the single-spiking phenotype is seen in a third of cells (Dickie et al 2019); it is possible that neurons expressing this peptide more sparse or absent in the TNc.…”

Section: Tonic Phasic and Delayed Cellsmentioning

confidence: 99%

Properties of neurons in the superficial laminae of trigeminal nucleus caudalis

et al. 2019

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The trigeminal nucleus caudalis ( TN c) receives extensive afferent innervation from peripheral sensory neurons of the trigeminal ganglion (TG), and is the first central relay in the circuitry underpinning orofacial pain. Despite the initial characterization of the neurons in the superficial laminae, many questions remain. Here we report on electrophysiological properties of 535 superficial lamina I/ II TN c neurons. Based on their firing pattern, we assigned these cells to five main groups, including (1) tonic, (2) phasic, (3) delayed, (4) H‐current, and (5) tonic‐phasic neurons, groups that exhibit distinct intrinsic properties and share some similarity with groups identified in the spinal dorsal horn. Driving predominantly nociceptive TG primary afferents using optogenetic stimulation in TRPV 1/ChR2 animals, we found that tonic and H‐current cells are most likely to receive pure monosynaptic input, whereas delayed neurons are more likely to exhibit inputs that appear polysynaptic. Finally, for the first time in TN c neurons, we used unsupervised clustering analysis methods and found that the kinetics of the action potentials and other intrinsic properties of these groups differ significantly from one another. Unsupervised spectral clustering based solely on a single voltage response to rheobase current was sufficient to group cells with shared properties independent of action potential discharge pattern, indicating that this approach can be effectively applied to identify functional neuronal subclasses. Together, our data illustrate that cells in the TN c with distinct patterns of TRPV 1/ChR2 afferent innervation are physiologically diverse, but can be understood as a few major groups of cells having shared functional properties.

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Ablation of spinal cord estrogen receptor α‐expressing interneurons reduces chemically induced modalities of pain and itch

Tran

Bráz

Hamel

et al. 2020

J of Comparative Neurology

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Estrogens are presumed to underlie, at least in part, the greater pain sensitivity and chronic pain prevalence that women experience compared to men. Although previous studies revealed populations of estrogen receptor-expressing neurons in primary afferents and in superficial dorsal horn neurons, there is little to no information as to the contribution of these neurons to the generation of acute and chronic pain. Here we molecularly characterized neurons in the mouse superficial spinal cord dorsal horn that express estrogen receptor α (ERα) and explored the behavioral consequences of their ablation. We found that spinal ERα-positive neurons are largely excitatory interneurons and many coexpress substance P, a marker for a discrete subset of nociceptive, excitatory interneurons. After viral, caspase-mediated ablation of spinal ERαexpressing cells, we observed a significant decrease in the first phase of the formalin test, but in male mice only. ERα-expressing neuron-ablation also reduced pruritogen-induced scratching in both male and female mice. There were no ablation-related changes in mechanical or heat withdrawal thresholds or in capsaicin-induced nocifensive behavior.In chronic pain models, we found no change in Complete Freund's adjuvant-induced thermal or mechanical hypersensitivity, or in partial sciatic nerve injury-induced mechanical allodynia. We conclude that ERα labels a subpopulation of excitatory interneurons that are specifically involved in chemically evoked persistent pain and pruritogen-induced itch.

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Morphological and functional properties distinguish the substance P and gastrin-releasing peptide subsets of excitatory interneuron in the spinal cord dorsal horn

Cited by 66 publications

References 75 publications

Expression of cholecystokinin by neurons in mouse spinal dorsal horn

Expression of cholecystokinin by neurons in mouse spinal dorsal horn

Properties of neurons in the superficial laminae of trigeminal nucleus caudalis

Ablation of spinal cord estrogen receptor α‐expressing interneurons reduces chemically induced modalities of pain and itch

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