Paulino Barragán‐Iglesias

The University of Texas at Dallas

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Vinicio Granados‐Soto

Center for Research and Advanced Studies of the National Polytechnic Institute

Theodore J. Price

The University of Texas at Dallas

Jorge Baruch Pineda-Farías

University of Pittsburgh

Gregory Dussor

The University of Texas at Dallas

Salim Megat

Inserm

Pradipta Ray

Bristol-Myers Squibb (United States)

Zachary T. Campbell

University of Wisconsin–Madison

Jamie K. Moy

University of Pittsburgh

Tzu‐Fang Lou

The University of Texas at Dallas

Andi Wangzhou

The University of Texas at Dallas

Cooperative Institutions

The University of Texas at Dallas

Center for Research and Advanced Studies of the National Polytechnic Institute

Instituto Politécnico Nacional

Universidad Nacional Autónoma de México

University of Arizona

Centro de Investigación en Materiales Avanzados

Autonomous University of Aguascalientes

The University of Texas Southwestern Medical Center

Instituto Nacional de Neurología y Neurocirugía

Carolinas Center for Advanced Management of Pain

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The l‐kynurenine–probenecid combination reduces neuropathic pain in rats

European Journal of Pain (2013)

Jorge Baruch Pineda-Farías Francisca Pérez‐Severiano Dinora F. González‐Esquivel Paulino Barragán‐Iglesias Mariana Bravo‐Hernández

Abstract Background l ‐ K ynurenine has antinociceptive effects in acute and inflammatory pain. This study determined the effect of l ‐kynurenine and its metabolite (kynurenic acid) on rats subjected to neuropathic pain. Methods L5/L6 spinal nerve ligation induced tactile allodynia as measured with von F rey filaments using the up‐down method. High‐performance liquid chromatography and W estern blot analysis determined kynurenic acid levels and expression of kynurenine amino transferase II (KAT II), respectively. Results l ‐Kynurenine (50–200 mg/kg, i.p.) or probenecid (100 mg/kg, i.p.) did not affect allodynia in neuropathic rats. In contrast, l ‐kynurenine (50–200 mg/kg, i.p.) in combination with probenecid (100 mg/kg, i.p.), an inhibitor of organic anion transport, reversed allodynia. Furthermore, intrathecal kynurenic acid (1–30 μg) reversed allodynia. Probenecid (100 mg/kg, i.p.) supplementation enhanced the maximal antiallodynic effect of intrathecal kynurenic acid (10 μg). Only the combined administration of l ‐kynurenine (200 mg/kg)/probenecid (100 mg/kg) increased the kynurenic acid concentration in cerebrospinal fluid. KAT II is expressed in dorsal root ganglia and dorsal spinal cord. KAT II expression was unchanged by the spinal nerve ligation or l ‐kynurenine/probenecid combination. The kynurenine/probenecid combination did not affect motor activity. Conclusions l ‐Kynurenine produces its antiallodynic effect in the central nervous system through kynurenic acid. This effect may result from blockade of N ‐methyl‐ d ‐aspartate receptors. KAT II is expressed in dorsal root ganglion and dorsal spinal cord. Combined l ‐kynurenine and probenecid therapy has the potential to reduce neuropathic pain in humans.

Kynurenic acid

Probenecid

Allodynia

10.1002/j.1532-2149.2013.00305.x

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Sex‐dependent pronociceptive role of spinal α₅‐GABA_A receptor and its epigenetic regulation in neuropathic rodents

Journal of Neurochemistry (2020)

Úrzula Franco‐Enzástiga Guadalupe García Janet Murbartián Rodrigo González‐Barrios Ana Belen Salinas-Abarca

Extrasynaptic α5 -subunit containing GABAA (α5 -GABAA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α5 -GABAA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by α5 -GABAA receptor inverse agonist intrathecal administration, L-655,708. The drug produced an antiallodynic effect in nerve-injured female rats and mice, and a lower effect in males. We hypothesized that changes in α5 -GABAA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased α5 -GABAA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over α5 -GABAA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17β-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α5 -GABAA receptor and estrogen receptor α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α5 -GABAA receptor down-regulation in males, we examined CpG island DNA methylation of α5 -GABAA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α5 -GABAA receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that α5 -GABAA receptor is a suitable target to treat chronic pain in females.

Allodynia

GABAB receptor

Nerve Injury

10.1111/jnc.15140

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Citations (36)

Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Andi Wangzhou Lisa A. McIlvried Candler Paige Paulino Barragán‐Iglesias Carolyn A. Guzman

Abstract Dorsal root ganglion (DRG) neurons detect sensory inputs and are crucial for pain processing. They are often studied in vitro as dissociated cell cultures with the assumption that this reasonably represents in vivo conditions. However, to our knowledge, no study has ever directly compared genome-wide transcriptomes of DRG tissue in vivo versus in vitro , or between different labs and culturing protocols. We extracted bilateral lumbar DRG from C57BL6/J mice and human organ donors, and acutely froze one side and processed the other side as a dissociated cell culture, which was then maintained in vitro for 4 days. RNA was extracted and sequenced using the NextSeq Illumina platform. Comparing native to cultured human or mouse DRG, we found that the overall expression level of many ion channels and GPCRs specifically expressed in neurons is markedly lower in culture, but still expressed. This suggests that most pharmacological targets expressed in vivo are present in culture conditions. However, there are changes in expression levels for these genes. The reduced relative expression for neuronal genes in human DRG cultures is likely accounted for by increased expression of genes in fibroblast-like and other proliferating cells, consistent with the mitotic status of many cells in these cultures. We did find a subset of genes that are typically neuronally expressed, increased in human and mouse DRG cultures, including genes associated with nerve injury and/or inflammation in preclinical models such as BDNF , MMP9 , GAL, and ATF3 . We also found a striking upregulation of a number of inflammation-associated genes in DRG cultures, although many were different between mouse and human. Our findings suggest an injury-like phenotype in DRG cultures that has important implications for the use of this model system for pain drug discovery.

Dorsal root ganglion

ATF3

10.1101/766865

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Citations (5)

Spinal 5-HT5A receptors mediate 5-HT-induced antinociception in several pain models in rats

Pharmacology Biochemistry and Behavior (2014)

Enriqueta Muñoz‐Islas Guadalupe C. Vidal‐Cantú Mariana Bravo‐Hernández Claudia Cervantes‐Durán Geovanna Nallely Quiñonez‐Bastidas

Dorsal root ganglion

Capsaicin

10.1016/j.pbb.2014.02.001

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Citations (39)

The impact of inflammatory mediators on the landscape of nascent translation in the dorsal root ganglion.

Journal of Pain (2021)

June Bryan de la Peña Paulino Barragán‐Iglesias Tzu‐Fang Lou Sarah Loerch Nikesh Kunder

Dorsal root ganglion

Ribosome profiling

10.1016/j.jpain.2021.03.024

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Spinal 5-HT 4 and 5-HT 6 receptors contribute to the maintenance of neuropathic pain in rats

Pharmacological Reports (2017)

Jorge Baruch Pineda-Farías Paulino Barragán‐Iglesias Alann Valdivieso-Sánchez Juan Rodrı́guez-Silverio Francisco Javier Flores‐Murrieta

Spinal nerve

Allodynia

Nerve Injury

10.1016/j.pharep.2017.04.001

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Citations (22)

Challenges and Opportunities for Early Career Researchers: Perspectives from the Ibro Early Career Committee

Olamide Elizabeth Adebiyi Paulino Barragán‐Iglesias Arjun Krishnaswamy Gwladys Temkou Ngoupaye Jacque Pak Kan Ip

The transition from postdoctoral training to setting up an independent laboratory is the favored academic career path. However, early career scientists often do not have the adequate training to advance to this next phase in their career. In addition to beginning and consolidating an independent line of research, early career scientists must hire personnel, obtain funding, teach, hire personnel and undertake administrative duties. In addition, this crucial phase often coincides with raising a family and caring responsibilities. How does one juggle professional and personal commitments during their formative years? In this article, the IBRO Early Career Committee, discusses the challenges faced by early career researchers (ECRs) across different geographies to inspire a support structure for the next generation of scientists

10.2139/ssrn.4524596

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Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

Journal of Neuroscience (2019)

Salim Megat Pradipta Ray Diana Tavares‐Ferreira Jamie K. Moy Ishwarya Sankaranarayanan

Nociceptors located in the trigeminal ganglion (TG) and DRG are the primary sensors of damaging or potentially damaging stimuli for the head and body, respectively, and are key drivers of chronic pain states. While nociceptors in these two tissues show a high degree of functional similarity, there are important differences in their development lineages, their functional connections to the CNS, and recent genome-wide analyses of gene expression suggest that they possess some unique genomic signatures. Here, we used translating ribosome affinity purification to comprehensively characterize and compare mRNA translation in Scn10a-positive nociceptors in the TG and DRG of male and female mice. This unbiased method independently confirms several findings of differences between TG and DRG nociceptors described in the literature but also suggests preferential utilization of key signaling pathways. Most prominently, we provide evidence that translational efficiency in mechanistic target of rapamycin (mTOR)-related genes is higher in the TG compared with DRG, whereas several genes associated with the negative regulator of mTOR, AMP-activated protein kinase, have higher translational efficiency in DRG nociceptors. Using capsaicin as a sensitizing stimulus, we show that behavioral responses are greater in the TG region and this effect is completely reversible with mTOR inhibition. These findings have implications for the relative capacity of these nociceptors to be sensitized upon injury. Together, our data provide a comprehensive, comparative view of transcriptome and translatome activity in TG and DRG nociceptors that enhances our understanding of nociceptor biology. SIGNIFICANCE STATEMENT The DRG and trigeminal ganglion (TG) provide sensory information from the body and head, respectively. Nociceptors in these tissues are critical first neurons in the pain pathway. Injury to peripheral neurons in these tissues can cause chronic pain. Interestingly, clinical and preclinical findings support the conclusion that injury to TG neurons is more likely to cause chronic pain and chronic pain in the TG area is more intense and more difficult to treat. We used translating ribosome affinity purification technology to gain new insight into potential differences in the translatomes of DRG and TG neurons. Our findings demonstrate previously unrecognized differences between TG and DRG nociceptors that provide new insight into how injury may differentially drive plasticity states in nociceptors in these two tissues.

Nociceptor

Dorsal root ganglion

Trigeminal ganglion

10.1523/jneurosci.2663-18.2019

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Citations (85)

Evaluation of the neonatal streptozotocin model of diabetes in rats: Evidence for a model of neuropathic pain

Pharmacological Reports (2017)

Paulino Barragán‐Iglesias Víctor Hugo Oidor-Chan Emanuel Loeza‐Alcocer Jorge Baruch Pineda-Farías Isabel Velázquez‐Lagunas

ATF3

Allodynia

10.1016/j.pharep.2017.09.002

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Citations (32)

Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55

Frontiers in Pharmacology (2019)

Raquel Guerrero‐Alba Paulino Barragán‐Iglesias Abimael González‐Hernández Eduardo E. Valdez-Moráles Vinicio Granados‐Soto

Background: Marijuana extracts (cannabinoids) are used since several millennia for pain treatment. Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB1 and CB2) have been deeply studied and classified. Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB1/CB2 receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors. Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors. According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration. Methods: This article reviews select relevant information about the potential role of GPR18 and GPR55 in the pathophysiology of pain. Results: This work summarized novel data supporting that, besides cannabinoid type-1 (CB1) and cannabinoid type-2 (CB2) receptors, GPR18 and GPR55 may be useful for pain treatment. Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55.

GPR18

Cannabinoid receptor antagonist

Synthetic cannabinoids

10.3389/fphar.2018.01496

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Citations (86)