Blockade of spinal α5-GABAA receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats

Luz-Cuellar, Yarim Elideth De la; Rodríguez‐Palma, Erick J.; Franco-Enzástiga, Úrzula; Salinas-Abarca, Ana Belen; Delgado‐Lezama, Rodolfo; Granados‐Soto, Vinicio

doi:10.1016/j.ejphar.2019.172443

Cited by 30 publications

(29 citation statements)

References 44 publications

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“…DRG neuron cultures, which to a certain extent represent an axotomy model per se, also develop increased GABA A current densities with time in culture (Lee et al, 2012). Other pain models such as formalin or reserpine injections are associated with upregulated α5 mRNA and protein expression in DRGs and spinal cord, and peripheral or intrathecal administration of an α5 antagonist prevents and reverses mechanical hypersensitivity (Bravo-Hernandez et al, 2016;De la Luz-Cuellar et al, 2019). Albeit there is an increasing body of data, the contribution of GABA A receptors in nociceptors to pathological pain is still controversial.…”

Section: Ligand-gated Chloride Channelsmentioning

confidence: 99%

Chloride – The Underrated Ion in Nociceptors

et al. 2020

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In contrast to pain processing neurons in the spinal cord, where the importance of chloride conductances is already well established, chloride homeostasis in primary afferent neurons has received less attention. Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na +-K +-2Cl − cotransporter 1 (NKCC1) and K +-Cl − cotransporter 2 (KCC2). Whereas in other cell types activation of chloride conductances causes hyperpolarization, activation of the same conductances in primary afferent neurons may lead to inhibitory or excitatory depolarization depending on the actual chloride reversal potential and the total amount of chloride efflux during channel or transporter activation. Dorsal root ganglion (DRG) neurons express a multitude of chloride channel types belonging to different channel families, such as ligand-gated, ionotropic γ-aminobutyric acid (GABA) or glycine receptors, Ca 2+-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweetyhomolog family, CLC chloride channels and transporters, cystic fibrosis transmembrane conductance regulator (CFTR) as well as volume-regulated anion channels (VRACs). Specific chloride conductances are involved in signal transduction and amplification at the peripheral nerve terminal, contribute to excitability and action potential generation of sensory neurons, or crucially shape synaptic transmission in the spinal dorsal horn. In addition, chloride channels can be modified by a plethora of inflammatory mediators affecting them directly, via protein-protein interaction, or through signaling cascades. Since chloride channels as well as mediators that modulate chloride fluxes are regulated in pain disorders and contribute to nociceptor excitation and sensitization it is timely and important to emphasize their critical role in nociceptive primary afferents in this review.

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Section: Ligand-gated Chloride Channelsmentioning

confidence: 99%

Chloride – The Underrated Ion in Nociceptors

et al. 2020

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“…Interestingly, the phasic excitability of primary afferent fibers mediated by the activation of synaptic α 2/3 GABA A Rs was not affected by L-655,708, while the tonic excitability mediated by extrasynaptic α 5 GABA A Rs was increased (Figure 2; Hernández-Reyes et al, 2019). Therefore, this result, together with the action of the α 5 GABA A R siRNA in healthy and reserpine-induced fibromyalgia (De la Luz-Cuellar et al, 2019), confirms the antinociceptive and pronociceptive role of α 5 GABA A Rs in healthy and chronic pain conditions, respectively.…”

Section: How Selective Is L -655708?mentioning

confidence: 76%

The role of spinal cord extrasynaptic α ₅ GABA _A receptors in chronic pain

et al. 2021

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“…Yet, a vast number of studies in animal models have causally implicated alterations in serotonin and noradrenaline neurotransmission in the genesis of persistent pain (for an extensive review please see (28)). For instance, serotonin and noradrenaline depletion through repeated administration of reserpine in rodents is sufficient to induce patterns of persistent tactile allodynia and it has recently been used as a fibromyalgia-like animal model for research on disease mechanisms and drug development (29)(30)(31)(32). Second, both the serotonin and noradrenaline transporters are targeted by drugs currently prescribed to control pain in patients with chronic pain, such as tricyclic antidepressants or non-selective inhibitors of the reuptake of serotonin and noradrenaline (20).…”

Section: Discussionmentioning

confidence: 99%

A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain

Martins

Veronese

Turkheimer

et al. 2021

Preprint

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Background: Chronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI (fMRI) has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, fMRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response. Methods: Here, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) to investigate whether neurotransmission-enriched functional connectivity (FC) mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. Chronic knee osteoarthritis (OA) pain patients (n=56) underwent pre-treatment brain scans in two clinical trials. Study 1 (n=17) was a 2-week single-blinded placebo pill trial. Study 2 (n=39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor. Results: Across two independent studies, we found that chronic pain OA patients present FC alterations in the FC related to the serotonin (SERT) and noradrenaline (NET) transporters, when compared to age-matched healthy controls. Placebo responders presented with higher pre-treatment dopamine transporter (DAT)-enriched FC than non-responders. Duloxetine responders presented with higher pre-treatment SERT and NET-enriched FC than non-responders. Pre-treatment SERT and NET-enriched FC achieved predictive positive values of duloxetine response up to 85.71%. Conclusion: Neurotransmission-enriched FC mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.

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Blockade of spinal α5-GABAA receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats

Cited by 30 publications

References 44 publications

Chloride – The Underrated Ion in Nociceptors

Chloride – The Underrated Ion in Nociceptors

The role of spinal cord extrasynaptic α ₅ GABA _A receptors in chronic pain

A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain

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Blockade of spinal α5-GABAA receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats

Cited by 30 publications

References 44 publications

Chloride – The Underrated Ion in Nociceptors

Chloride – The Underrated Ion in Nociceptors

The role of spinal cord extrasynaptic α 5 GABA A receptors in chronic pain

A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain

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Product

Resources

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The role of spinal cord extrasynaptic α ₅ GABA _A receptors in chronic pain