Hyperpolarization‐activated channels shape temporal patterns of ectopic spontaneous discharge in C‐nociceptors after peripheral nerve injury

Bernal, Laura; Roza, Carolina

doi:10.1002/ejp.1226

Cited by 16 publications

(13 citation statements)

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“…In mouse nociceptors, block of both EPAC isoforms is necessary to block the hyperactivity, either by combining two EPAC inhibitors or an inhibitor for one isoform with genetic deletion of the second isoform (red x). The necessity of PKA in rat nociceptors for hyperactivity after SCI was reported previously (Bavencoffe et al, 2016), while the necessity of HCN channels for similar hyperexcitability has been reported in other injury models (Bernal and Roza, 2018, Djouhri et al, 2015, Djouhri et al, 2018, Emery et al, 2011, Young et al, 2014) and observed after SCI (A.G. Bavencoffe, C.W. Dessauer and E.T.…”

Section: Discussionsupporting

confidence: 73%

EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury

Berkey

Herrera

Odem

et al. 2020

Neurobiology of Pain

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Chronic pain following spinal cord injury (SCI) is associated with electrical hyperactivity (spontaneous and evoked) in primary nociceptors. Cyclic adenosine monophosphate (cAMP) signaling is an important contributor to nociceptor excitability, and knockdown of the cAMP effector, exchange protein activated by cAMP (EPAC), has been shown to relieve pain-like responses in several chronic pain models. To examine potentially distinct roles of each EPAC isoform (EPAC1 and 2) in maintaining chronic pain, we used rat and mouse models of contusive spinal cord injury (SCI). Pharmacological inhibition of EPAC1 or 2 in a rat SCI model was sufficient to reverse SCI-induced nociceptor hyperactivity, indicating that EPAC1 and 2 signaling activity are complementary, with both required to maintain hyperactivity. However, EPAC activation was not sufficient to induce similar hyperactivity in nociceptors from naïve rats, and we observed no change in EPAC protein expression after SCI. In the mouse SCI model, inhibition of both EPAC isoforms through a combination of pharmacological inhibition and genetic deletion was required to reverse SCI-induced nociceptor hyperactivity. This was consistent with our finding that neither EPAC1−/− nor EPAC2−/− mice were protected against SCI-induced chronic pain as assessed with an operant mechanical conflict test. Thus, EPAC1 and 2 activity may play a redundant role in mouse nociceptors, although no corresponding change in EPAC protein expression levels was detected after SCI. Despite some differences between these species, our data demonstrate a fundamental role for both EPAC1 and EPAC2 in mechanisms maintaining nociceptor hyperactivity and chronic pain after SCI.

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Section: Discussionsupporting

confidence: 73%

EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury

Berkey

Herrera

Odem

et al. 2020

Neurobiology of Pain

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“…Demyelination allows for ectopic relocation of Na v and K v channels along the exposed patches of axonal membrane, altering the normal excitability and prompting abnormal spontaneous firing of action potentials (Roza et al, 2003; Campbell and Meyer, 2006; Bernal et al, 2016; Bernal and Roza, 2018; Roza and Lopez-Garcia, 2008). In addition, loss of myelin could favor electrical coupling between fibers (Meyer et al, 1985; Bernal et al, 2016) and promote aberrant sprouting from demyelinated nodes (Griffin et al, 2010).…”

Section: Lpa and Neuropathic Painmentioning

confidence: 99%

Lysophosphatidic Acid and Glutamatergic Transmission

Roza

Campos-Sandoval

Gómez-García

et al. 2019

Front. Mol. Neurosci.

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Signaling through bioactive lipids regulates nervous system development and functions. Lysophosphatidic acid (LPA), a membrane-derived lipid mediator particularly enriched in brain, is able to induce many responses in neurons and glial cells by affecting key processes like synaptic plasticity, neurogenesis, differentiation and proliferation. Early studies noted sustained elevations of neuronal intracellular calcium, a primary response to LPA exposure, suggesting functional modifications of NMDA and AMPA glutamate receptors. However, the crosstalk between LPA signaling and glutamatergic transmission has only recently been shown. For example, stimulation of presynaptic LPA receptors in hippocampal neurons regulates glutamate release from the presynaptic terminal, and excess of LPA induce seizures. Further evidence indicating a role of LPA in the modulation of neuronal transmission has been inferred from animal models with deficits on LPA receptors, mainly LPA 1 which is the most prevalent receptor in human and mouse brain tissue. LPA 1 null-mice exhibit cognitive and attention deficits characteristic of schizophrenia which are related with altered glutamatergic transmission and reduced neuropathic pain. Furthermore, silencing of LPA 1 receptor in mice induced a severe down-regulation of the main glutaminase isoform (GLS) in cerebral cortex and hippocampus, along with a parallel sharp decrease on active matrix-metalloproteinase 9. The downregulation of both enzymes correlated with an altered morphology of glutamatergic pyramidal cells dendritic spines towards a less mature phenotype, indicating important implications of LPA in synaptic excitatory plasticity which may contribute to the cognitive and memory deficits shown by LPA 1 -deficient mice. In this review, we present an updated account of current evidence pointing to important implications of LPA in the modulation of synaptic excitatory transmission.

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“…For electrophysiological recordings, saphenous spared nerve injury was performed (SSNI) as it allows the simultaneous study of axotomized and non‐axotomized fibres with intact receptive fields (RFs) within the same ex vivo preparation and that produces a large number of fibres with ectopic spontaneous and evoked discharges as previously described (Bernal et al., 2016; Bernal & Roza, 2018). Briefly, nerve‐end neuromas were produced by a total section of one of the peripheral branches of the saphenous nerve.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have pointed out that the expression of regeneration associated genes might not be restricted to axotomized neurons, as shown for the increased expression of activating transcription factor 3 (ATF) in non‐injured neurons after spared nerve injury (SNI) in rats (Berta et al., 2017). Moreover, electrophysiological and behavioural studies in models of incomplete nerve injury have revealed abnormal functional properties in intact fibres as well as the development of hyperalgesia independent of injured fibres (Ali et al., 1999; Bernal et al., 2016; Bernal & Roza, 2018; Li et al., 2000; Michaelis et al., 2000; Wu et al., 2001).…”

Section: Introductionmentioning

confidence: 99%

Activation of the regeneration‐associated gene STAT3 and functional changes in intact nociceptors after peripheral nerve damage in mice

Bernal

Cisneros

Roza

2021

European Journal of Pain

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Background In the context of neuropathic pain, the contribution of regeneration to the development of positive symptoms is not completely understood. Several efforts have been done to described changes in axotomized neurons, however, there is scarce data on changes occurring in intact neurons, despite experimental evidence of functional changes. To address this issue, we analysed by immunohistochemistry the presence of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), an accepted marker of regeneration, within DRGs where axotomized neurons were retrogradely labelled following peripheral nerve injury. Likewise, we have characterized abnormal electrophysiological properties in intact fibres after partial nerve injury. Methods/Results We showed that induction of pSTAT3 in sensory neurons was similar after partial or total transection of the sciatic nerve and to the same extent within axotomized and non‐axotomized neurons. We also examined pSTAT3 presence on non‐peptidergic and peptidergic nociceptors. Whereas the percentage of neurons marked by IB4 decrease after injury, the proportion of CGRP neurons did not change, but its expression switched from small‐ to large‐diameter neurons. Besides, the percentage of CGRP+ neurons expressing pSTAT3 increased significantly 2.5‐folds after axotomy, preferentially in neurons with large diameters. Electrophysiological recordings showed that after nerve damage, most of the neurons with ectopic spontaneous activity (39/46) were non‐axotomized C‐fibres with functional receptive fields in the skin far beyond the site of damage. Conclusions Neuronal regeneration after nerve injury, likely triggered from the site of injury, may explain the abnormal functional properties gained by intact neurons, reinforcing their role in neuropathic pain. Significance Positive symptoms in patients with peripheral neuropathies correlate to abnormal functioning of different subpopulations of primary afferents. Peripheral nerve damage triggers regenerating programs in the cell bodies of axotomized but also in non‐axotomized nociceptors which is in turn, develop abnormal spontaneous and evoked discharges. Therefore, intact nociceptors have a significant role in the development of neuropathic pain due to their hyperexcitable peripheral terminals. Therapeutical targets should focus on inhibiting peripheral hyperexcitability in an attempt to limit peripheral and central sensitization.

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Hyperpolarization‐activated channels shape temporal patterns of ectopic spontaneous discharge in C‐nociceptors after peripheral nerve injury

Cited by 16 publications

References 50 publications

EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury

EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury

Lysophosphatidic Acid and Glutamatergic Transmission

Activation of the regeneration‐associated gene STAT3 and functional changes in intact nociceptors after peripheral nerve damage in mice

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