Publications by authors named "Rohini Kuner"

111 Publications

Suppression of neuropathic pain and comorbidities by recurrent cycles of repetitive transcranial direct current motor cortex stimulation in mice.

Sci Rep 2021 May 6;11(1):9735. Epub 2021 May 6.

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. However, there is a major need for improving efficacy, reducing variability and understanding mechanisms. Rodent models hold promise in helping to overcome these obstacles. However, there still remains a major divide between clinical and preclinical studies with respect to stimulation programs, analysis of pain as a multidimensional sensory-affective-motivational state and lack of focus on chronic phases of established pain. Here, we employed direct transcranial M1 stimulation (M1 tDCS) either as a single 5-day block or recurring blocks of repetitive stimulation over early or chronic phases of peripherally-induced neuropathic pain in mice. We report that repeated blocks of stimulation reverse established neuropathic mechanical allodynia more strongly than a single 5-day regime and also suppress cold allodynia, aversive behavior and anxiety without adversely affecting motor function over a long period. Activity mapping revealed highly selective alterations in the posterior insula, periaqueductal gray subdivisions and superficial spinal laminae in reversal of mechanical allodynia. Our preclinical data reveal multimodal analgesia and improvement in quality of life by multiple blocks of M1 tDCS and uncover underlying brain networks, thus helping promote clinical translation.
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http://dx.doi.org/10.1038/s41598-021-89122-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102487PMC
May 2021

Locus revealed: Painlessness via loss of Na1.7 at central terminals of sensory neurons.

Neuron 2021 May;109(9):1413-1416

Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address:

How genetic loss of the sodium channel Na1.7 results in painlessness is puzzling. MacDonald et al. (2021) demonstrate that instead of impairing peripheral excitability, Na1.7 channels at central terminals of pain-sensing afferents play a pivotal role in the balance between pain and analgesia.
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http://dx.doi.org/10.1016/j.neuron.2021.04.011DOI Listing
May 2021

Repetitive non-invasive prefrontal stimulation reverses neuropathic pain via neural remodelling in mice.

Prog Neurobiol 2021 Jun 20;201:102009. Epub 2021 Feb 20.

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address:

Chronic neuropathic pain presents a major challenge to pharmacological therapy and neurostimulation-based alternatives are gaining interest. Although invasive and non-invasive motor cortex stimulation has been the focus of several studies, very little is known about the potential of targeting the prefrontal cortex. This study was designed to elucidate the analgesic potential of prefrontal stimulation in a translational context and to uncover the neural underpinnings thereof. Here, we report that non-invasive, repetitive direct anodal current transcranial stimulation (tDCS) of the prefrontal cortex exerted analgesia in mice with neuropathic pain for longer than a week. When applied at chronic stages of neuropathic pain, prefrontal tDCS reversed established allodynia and suppressed aversion and anxiety-related behaviours. Activity mapping as well as in vivo electrophysiological analyses revealed that although the cortex responds to acute tDCS with major excitation, repetitive prefrontal tDCS brings about large-scale silencing of cortical activity. Different classes of different classes of GABAergic interneurons and classes of excitatory neurons differs dramatically between single, acute vs and repetitive tDCS. Repetitive prefrontal tDCS alters basal activity as well as responsivity of a discrete set of distant cortical and sub-cortical areas to tactile stimuli, namely the rostral anterior cingulate cortex, the insular cortex, the ventrolateral periaqueductal grey and the spinal dorsal horn. This study thus makes a strong case for harnessing prefrontal cortical modulation for non-invasive transcranial stimulation paradigms to achieve long-lasting pain relief in established neuropathic pain states and provides valuable insights gained on neural mechanistic underpinnings of prefrontal tDCS in neuropathic pain.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102009DOI Listing
June 2021

Publisher Correction: Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy.

Nat Commun 2021 Feb 8;12(1):989. Epub 2021 Feb 8.

Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany.

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http://dx.doi.org/10.1038/s41467-021-21406-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870942PMC
February 2021

A genome-wide screen reveals microRNAs in peripheral sensory neurons driving painful diabetic neuropathy.

Pain 2021 May;162(5):1334-1351

Department of Molecular Pharmacology, Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany. Dr. Bali is now with the Department of Experimental Pain Research, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Abstract: Diabetes is a leading cause of peripheral neuropathy (diabetic peripheral neuropathy, DPN), and uncontrolled long-lasting hyperglycemia leads to severe complications. A major proportion of diabetics develop excruciating pain with a variable course. Mechanisms leading to painful DPN are not completely understood and treatment options limited. We hypothesized that epigenetic modulation at the level of microRNA (miRNA) expression triggered by metabolic imbalance and nerve damage regulates the course of pain development. We used clinically relevant preclinical models, genome-wide screening, in silico analyses, cellular assays, miRNA fluorescent in situ hybridization, in vivo molecular manipulations, and behavioral analyses in the current study. We identified miRNAs and their targets that critically impact on nociceptive hypersensitivity in painful DPN. Our analyses identify miR-33 and miR-380 expressed in nociceptive neurons as critical denominators of diabetic pain and miR-124-1 as a mediator of physiological nociception. Our comprehensive analyses on the putative mRNA targets for miR-33 or miR-124-1 identified a set of mRNAs that are regulated after miR-33 or miR-124-1 overexpression in dorsal root ganglia in vivo. Our results shed light on the regulation of DPN pathophysiology and implicate specific miRNAs as novel therapeutic targets for treating painful DPN.
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http://dx.doi.org/10.1097/j.pain.0000000000002159DOI Listing
May 2021

Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy.

Nat Commun 2021 01 18;12(1):426. Epub 2021 Jan 18.

Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany.

Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.
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http://dx.doi.org/10.1038/s41467-020-20677-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814083PMC
January 2021

SUMOylation of Enzymes and Ion Channels in Sensory Neurons Protects against Metabolic Dysfunction, Neuropathy, and Sensory Loss in Diabetes.

Neuron 2020 09 30;107(6):1141-1159.e7. Epub 2020 Jul 30.

Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address:

Diabetic peripheral neuropathy (DPN) is a highly frequent and debilitating clinical complication of diabetes that lacks therapies. Cellular oxidative stress regulates post-translational modifications, including SUMOylation. Here, using unbiased screens, we identified key enzymes in metabolic pathways and ion channels as novel molecular targets of SUMOylation that critically regulated their activity. Sensory neurons of diabetic patients and diabetic mice demonstrated changes in the SUMOylation status of metabolic enzymes and ion channels. In support of this, profound metabolic dysfunction, accelerated neuropathology, and sensory loss were observed in diabetic gene-targeted mice selectively lacking the ability to SUMOylate proteins in peripheral sensory neurons. TRPV1 function was impaired by diabetes-induced de-SUMOylation as well as by metabolic imbalance elicited by de-SUMOylation of metabolic enzymes, facilitating diabetic sensory loss. Our results unexpectedly uncover an endogenous post-translational mechanism regulating diabetic neuropathy in patients and mouse models that protects against metabolic dysfunction, nerve damage, and altered sensory perception.
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http://dx.doi.org/10.1016/j.neuron.2020.06.037DOI Listing
September 2020

Spinal Wnt5a Plays a Key Role in Spinal Dendritic Spine Remodeling in Neuropathic and Inflammatory Pain Models and in the Proalgesic Effects of Peripheral Wnt3a.

J Neurosci 2020 08 2;40(35):6664-6677. Epub 2020 Jul 2.

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany.

Wnt signaling represents a highly versatile signaling system, which plays critical roles in developmental morphogenesis as well as synaptic physiology in adult life and is implicated in a variety of neural disorders. Recently, we demonstrated that Wnt3a is able to recruit multiple noncanonical signaling pathways to alter peripheral sensory neuron function in a nociceptive modality-specific manner. Furthermore, several studies recently reported an important role for Wnt5a acting via canonical and noncanonical signaling in spinal processing of nociception in a number of pathologic pain disorders. Here, using diverse molecular, genetic, and behavioral approaches in mouse models of pain , we report a novel role for Wnt5a signaling in nociceptive modulation at the structural level. In models of chronic pain, using male and female mice, we found that Wnt5a is released spinally from peripheral sensory neurons, where it recruits the tyrosine kinase receptors Ror2 and Ryk to modulate dendritic spine rearrangement. Blocking the Wnt5a-Ryk/Ror2 axis in spinal dorsal horn neurons prevented activity-dependent dendritic spine remodeling and significantly reduced mechanical hypersensitivity induced by peripheral injury as well as inflammation. Moreover, we observed that peripheral Wnt3a signaling triggers the release of Wnt5a in the spinal cord, and inhibition of spinal Wnt5a signaling attenuates the functional impact of peripheral Wnt3a on nociceptive sensitivity. In conclusion, this study reports a novel role for the Wnt signaling axis in coordinating peripheral and spinal sensitization and shows that targeting Wnt5a-Ryk/ROR2 signaling alleviates both structural and functional mechanisms of nociceptive hypersensitivity in models of chronic pain There is a major need to elucidate molecular mechanisms underlying chronic pain disorders to develop novel therapeutic approaches. Wnt signaling represents a highly versatile signaling system, which plays critical roles during development and adult physiology, and it was implicated in several diseases, including chronic pain conditions. Using mouse models, our study identifies a novel role for Wnt5a signaling in nociceptive modulation at the spinal cord level. We observed that Wnt5a recruits Ror2 and Ryk receptors to enhance dendritic spine density, leading to nociceptive sensitization. Blocking the Wnt5a-Ryk/Ror2 interaction in the spinal dorsal horn prevented spine remodeling and significantly reduced inflammatory and neuropathic hypersensitivity. These findings provide proof-of-concept for targeting spinal Wnt signaling for alleviating nociceptive hypersensitivity .
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http://dx.doi.org/10.1523/JNEUROSCI.2942-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455212PMC
August 2020

Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain.

Mol Psychiatry 2020 Jul 1. Epub 2020 Jul 1.

Department of Clinical Neurobiology, University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany.

In mammals, most adult neural stem cells (NSCs) are located in the ventricular-subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior-ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.
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http://dx.doi.org/10.1038/s41380-020-0823-4DOI Listing
July 2020

Neuropathic Pain: From Mechanisms to Treatment.

Physiol Rev 2021 01 25;101(1):259-301. Epub 2020 Jun 25.

Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; and Department of Pharmacology, Heidelberg University, Heidelberg, Germany.

Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition with major impact on quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central poststroke pain. Most patients complain of an ongoing or intermittent spontaneous pain of, for example, burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in, for example, nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Evoked pain may spread to neighboring areas, and the underlying pathophysiology involves peripheral and central sensitization. Maladaptive structural changes and a number of cell-cell interactions and molecular signaling underlie the sensitization of nociceptive pathways. These include alteration in ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation. The major classes of therapeutics include drugs acting on αδ subunits of calcium channels, sodium channels, and descending modulatory inhibitory pathways.
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http://dx.doi.org/10.1152/physrev.00045.2019DOI Listing
January 2021

Clinically Actionable Strategies for Studying Neural Influences in Cancer.

Cancer Cell 2020 07 11;38(1):11-14. Epub 2020 Jun 11.

Center for Neuroscience at the University of Pittsburgh, Pittsburgh Center for Pain Research and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.
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http://dx.doi.org/10.1016/j.ccell.2020.05.023DOI Listing
July 2020

Cellular Circuits in the Brain and Their Modulation in Acute and Chronic Pain.

Physiol Rev 2021 01 11;101(1):213-258. Epub 2020 Jun 11.

Institute of Pharmacology, Heidelberg University, Heidelberg, Germany; and Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.

Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating, or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics, and imaging technological tools in rodent models with a view towards decoding sensory, affective, and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward, and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic, and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.
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http://dx.doi.org/10.1152/physrev.00040.2019DOI Listing
January 2021

Characterization of experimental diabetic neuropathy using multicontrast magnetic resonance neurography at ultra high field strength.

Sci Rep 2020 05 5;10(1):7593. Epub 2020 May 5.

Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, INF 410, Heidelberg, Germany.

In light of the limited treatment options of diabetic polyneuropathy (DPN) available, suitable animal models are essential to investigate pathophysiological mechanisms and to identify potential therapeutic targets. In vivo evaluation with current techniques, however, often provides only restricted information about disease evolution. In the study of patients with DPN, magnetic resonance neurography (MRN) has been introduced as an innovative diagnostic tool detecting characteristic lesions within peripheral nerves. We developed a novel multicontrast ultra high field MRN strategy to examine major peripheral nerve segments in diabetic mice non-invasively. It was first validated in a cross-platform approach on human nerve tissue and then applied to the popular streptozotocin(STZ)-induced mouse model of DPN. In the absence of gross morphologic alterations, a distinct MR-signature within the sciatic nerve was observed mirroring subtle changes of the nerves' fibre composition and ultrastructure, potentially indicating early re-arrangements of DPN. Interestingly, these signal alterations differed from previously reported typical nerve lesions of patients with DPN. The capacity of our approach to non-invasively assess sciatic nerve tissue structure and function within a given mouse model provides a powerful tool for direct translational comparison to human disease hallmarks not only in diabetes but also in other peripheral neuropathic conditions.
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http://dx.doi.org/10.1038/s41598-020-64585-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200726PMC
May 2020

CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients.

Gastroenterology 2020 08 21;159(2):665-681.e13. Epub 2020 Apr 21.

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany. Electronic address:

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by excruciating pain, which has been associated with attraction of cancer cells and their invasion of intrapancreatic sensory nerves. Neutralization of the chemokine CCL2 reduced cancer-associated pain in a clinical trial, but there have been no systematic analyses of the highly diverse chemokine families and their receptors in PDAC.

Methods: We performed an open, unbiased RNA-interference screen of mammalian chemokines in co-cultures of mouse PDAC cells (K8484) and mouse peripheral sensory neurons, and confirmed findings in studies of DT8082 PDAC cells. We studied the effects of chemokines on migration of PDAC cell lines. Orthotopic tumors were grown from K8484 cells in mice, and mice were given injections of neutralizing antibodies against chemokines, antagonists, or control antibodies. We analyzed abdominal mechanical hypersensitivity and collected tumors and analyzed them by histology and immunohistochemistry to assess neural remodeling. We collected PDAC samples and information on pain levels from 74 patients undergoing resection and measured levels of CXCR3 and CCR7 by immunohistochemistry and immunoblotting.

Results: Knockdown of 9 chemokines in DRG neurons significantly reduced migration of PDAC cells towards sensory neurons. Sensory neuron-derived CCL21 and CXCL10 promoted migration of PDAC cells via their receptors CCR7 and CXCR3, respectively, which were expressed by cells in orthotopic tumors and PDAC specimens from patients. Neutralization of CCL21 or CXCL10, or their receptors, in mice with orthotopic tumors significantly reduced nociceptive hypersensitivity and nerve fiber hypertrophy and improved behavioral parameters without affecting tumor infiltration by T cells or neutrophils. Increased levels of CXCR3 and CCR7 in human PDAC specimens were associated with increased frequency of cancer-associated pain, determined from patient questionnaires.

Conclusions: In an unbiased screen of chemokines, we identified CCL21 and CXCL10 as proteins that promote migration of pancreatic cancer cells toward sensory neurons. Inhibition of these chemokines or their receptors reduce hypersensitivity in mice with orthotopic tumors, and patients with PDACs with high levels of the chemokine receptors of CXCR3 and CCR7 had increased frequency of cancer-associated pain.
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http://dx.doi.org/10.1053/j.gastro.2020.04.037DOI Listing
August 2020

A common ground for pain and depression.

Nat Neurosci 2019 10;22(10):1612-1614

Pharmacology Institute, Heidelberg University, Heidelberg, Germany.

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http://dx.doi.org/10.1038/s41593-019-0499-8DOI Listing
October 2019

The impact of Semaphorin 4C/Plexin-B2 signaling on fear memory via remodeling of neuronal and synaptic morphology.

Mol Psychiatry 2021 04 23;26(4):1376-1398. Epub 2019 Aug 23.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

Aberrant fear is a cornerstone of several psychiatric disorders. Consequently, there is large interest in elucidation of signaling mechanisms that link extracellular cues to changes in neuronal function and structure in brain pathways that are important in the generation and maintenance of fear memory and its behavioral expression. Members of the Plexin-B family of receptors for class 4 semaphorins play important roles in developmental plasticity of neurons, and their expression persists in some areas of the adult nervous system. Here, we aimed to elucidate the role of Semaphorin 4C (Sema4C) and its cognate receptor, Plexin-B2, in the expression of contextual and cued fear memory, setting a mechanistic focus on structural plasticity and exploration of contributing signaling pathways. We observed that Plexin-B2 and Sema4C are expressed in forebrain areas related to fear memory, such as the anterior cingulate cortex, amygdala and the hippocampus, and their expression is regulated by aversive stimuli that induce fear memory. By generating forebrain-specific Plexin-B2 knockout mice and analyzing fear-related behaviors, we demonstrate that Sema4C-PlexinB2 signaling plays a crucial functional role in the recent and remote recall of fear memory. Detailed neuronal morphological analyses revealed that Sema4C-PlexinB2 signaling largely mediates fear-induced structural plasticity by enhancing dendritic ramifications and modulating synaptic density in the adult hippocampus. Analyses on signaling-related mutant mice showed that these functions are mediated by PlexinB2-dependent RhoA activation. These results deliver important insights into the mechanistic understanding of maladaptive plasticity in fear circuits and have implications for novel therapeutic strategies against fear-related disorders.
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http://dx.doi.org/10.1038/s41380-019-0491-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985029PMC
April 2021

Structure-function relationships in peripheral nerve contributions to diabetic peripheral neuropathy.

Pain 2019 05;160 Suppl 1:S29-S36

Department of Molecular Pharmacology, Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.

Diabetes mellitus (DM) is a major global health concern, affecting more than 9% of the world population. The most common complication of DM is diabetic peripheral neuropathy (DPN), which leads to neuropathic pain in as many as 50% of patients. Despite its prevalence, there is neither good prevention of nor treatments for DPN, representing a major gap in care for the many who are afflicted. It has long been known from patient studies that both small and large primary afferent fibers undergo structural changes in DPN; however, the exact functional contributions of these changes to DPN symptomology are unknown, necessitating animal studies. This review first presents the commonly used mouse models of DPN resulting from both type 1 and type 2 DM. It then discusses structural changes in Aβ, Aδ, and C fibers throughout the progression of DPN and their respective contributions to painful DPN in both human patients and DM mouse models. Finally, it highlights remaining questions on sensory neuron structure-function relationships in painful DPN and how we may address these in mouse models by using technological advances in cell-specific modulation. Only when these structure-function relationships are understood, can novel targeted therapeutics be developed for DPN.
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http://dx.doi.org/10.1097/j.pain.0000000000001530DOI Listing
May 2019

Metabolomic signature of type 1 diabetes-induced sensory loss and nerve damage in diabetic neuropathy.

J Mol Med (Berl) 2019 06 4;97(6):845-854. Epub 2019 Apr 4.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, D-69120, Heidelberg, Germany.

Diabetic-induced peripheral neuropathy (DPN) is a highly complex and frequent diabetic late complication, which is manifested by prolonged hyperglycemia. However, the molecular mechanisms underlying the pathophysiology of nerve damage and sensory loss remain largely unclear. Recently, alteration in metabolic flux has gained attention as a basis for organ damage in diabetes; however, peripheral sensory neurons have not been adequately analyzed with respect to metabolic dysfunction. In the present study, we attempted to delineate the sequence of event occurring in alteration of metabolic pathways in relation to nerve damage and sensory loss. C57Bl6/j wild-type mice were analyzed longitudinally up to 22 weeks in the streptozotocin (STZ) model of type 1 diabetes. The progression of DPN was investigated by behavioral measurements of sensitivity to thermal and mechanical stimuli and quantitative morphological assessment of intraepidermal nerve fiber density. We employed a mass spectrometry-based screen to address alterations in levels of metabolites in peripheral sciatic nerve and amino acids in serum over several months post-STZ administration to elucidate metabolic dysfunction longitudinally in relation to sensory dysfunction. Although hyperglycemia and body weight changes occurred early, sensory loss and reduced intraepithelial branching of nociceptive nerves were only evident at 22 weeks post-STZ. The longitudinal metabolites screen in peripheral nerves demonstrated that compared with buffer-injected age-matched control mice, mice at 12 and 22 weeks post-STZ showed an early impairment the tricaoboxylic acid (TCA cycle), which is the main pathway of carbohydrate metabolism leading to energy generation. We found that levels of citric acid, ketoglutaric acid (2 KG), succinic acid, fumaric acid, and malic acid were observed to be significantly reduced in sciatic nerve at 22 weeks post-STZ. In addition, we also found the increase in levels of sorbitol and L-lactate in peripheral nerve from 12 weeks post-STZ injection. Amino acid screen in serum showed that the amino acids valine (Val), isoleucine (Ile), and leucine (Leu), grouped together as BCAA, increased more than twofold from 12 weeks post-STZ. Similarly, the levels of tyrosine (Tyr), asparagine (Asn), serine (Ser), histidine (His), alanine (Ala), and proline (Pro) showed progressive increase with progression of diabetes. Our results indicate that the impaired TCA cycle metabolites in peripheral nerve are the primary cause of shunting metabolic substrate to compensatory pathways, which leads to sensory nerve fiber loss in skin and contribute to onset and progression of peripheral neuropathy.
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http://dx.doi.org/10.1007/s00109-019-01781-1DOI Listing
June 2019

Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception.

Nat Commun 2019 02 28;10(1):983. Epub 2019 Feb 28.

Pharmacology Institute, Medical Faculty Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex.
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http://dx.doi.org/10.1038/s41467-019-08873-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395755PMC
February 2019

Epigenetic control of hypersensitivity in chronic inflammatory pain by the de novo DNA methyltransferase Dnmt3a2.

Mol Pain 2019 Jan-Dec;15:1744806919827469

1 Department of Neurobiology, Interdisciplinary Centre for Neurosciences, Heidelberg University, Heidelberg, Germany.

Chronic pain is a pathological manifestation of neuronal plasticity supported by altered gene transcription in spinal cord neurons that results in long-lasting hypersensitivity. Recently, the concept that epigenetic regulators might be important in pathological pain has emerged, but a clear understanding of the molecular players involved in the process is still lacking. In this study, we linked Dnmt3a2, a synaptic activity-regulated de novo DNA methyltransferase, to chronic inflammatory pain. We observed that Dnmt3a2 levels are increased in the spinal cord of adult mice following plantar injection of Complete Freund's Adjuvant, an in vivo model of chronic inflammatory pain. In vivo knockdown of Dnmt3a2 expression in dorsal horn neurons blunted the induction of genes triggered by Complete Freund's Adjuvant injection. Among the genes whose transcription was found to be influenced by Dnmt3a2 expression in the spinal cord is Ptgs2, encoding for Cox-2, a prime mediator of pain processing. Lowering the levels of Dnmt3a2 prevented the establishment of long-lasting inflammatory hypersensitivity. These results identify Dnmt3a2 as an important epigenetic regulator needed for the establishment of central sensitization. Targeting expression or function of Dnmt3a2 may be suitable for the treatment of chronic pain.
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http://dx.doi.org/10.1177/1744806919827469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362517PMC
May 2019

Evoked hypoalgesia is accompanied by tonic pain and immune cell infiltration in the dorsal root ganglia at late stages of diabetic neuropathy in mice.

Mol Pain 2018 Jan-Dec;14:1744806918817975. Epub 2018 Nov 20.

Institute of Pharmacology, Heidelberg University, Germany.

Diabetic peripheral neuropathy is a major debilitating late complication of diabetes, which significantly reduces the quality of life in patients. Diabetic peripheral neuropathy is associated with a wide spectrum of sensory abnormalities, where in loss of sensation or hypoalgesia to applied external stimuli is paradoxically accompanied by debilitating tonic spontaneous pain. In numerous studies on animal models of diabetic peripheral neuropathy, behavioural measurements have been largely confined to analysis of evoked withdrawal to mechanical and thermal stimuli applied to dermatomes, whereas spontaneous, on-going pain has not been widely studied. In the Streptozotocin model of type 1 diabetes, we employed the Conditioned Place Preference test to assess tonic pain. Our results indicate that both phases, that is, early evoked hypersensitivity (i.e. 5-7 weeks post-Streptozotocin) as well as late stage hypoalgesia (i.e. 17-20 weeks post-Streptozotocin) are accompanied by significant tonic pain in mice with diabetic peripheral neuropathy. We also report on the temporal relation between on-going pain and neuropathological changes in the dorsal root ganglia of mice with diabetic peripheral neuropathy up to 6 months post-Streptozotocin. Neither early hypersensitivity nor late hypoalgesia were associated with markers of cellular stress in the dorsal root ganglia. Whereas significant neutrophil infiltration was observed in the dorsal root ganglia over both early and late stages post-Streptozotocin, T-cell infiltration in the dorsal root ganglia was prominent at late stages post-Streptozotocin. Thus, longitudinal analyses reveal that similar to patients with chronic diabetic peripheral neuropathy, mice show tonic pain despite sensory loss after several months in the Streptozotocin model, which is accompanied by neuroimmune interactions in the dorsal root ganglia.
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http://dx.doi.org/10.1177/1744806918817975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311571PMC
April 2019

Hypoxia-inducible factor 1α protects peripheral sensory neurons from diabetic peripheral neuropathy by suppressing accumulation of reactive oxygen species.

J Mol Med (Berl) 2018 12 25;96(12):1395-1405. Epub 2018 Oct 25.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, D-69120, Heidelberg, Germany.

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic complications. Mechanisms underlying nerve damage and sensory loss following metabolic dysfunction remain largely unclear. Recently, hyperglycemia-induced mitochondrial dysfunction and the generation of reactive oxygen species (ROS) have gained attention as possible mechanisms of organ damage in diabetes. Hypoxia-inducible factor 1 (HIF1α) is a key transcription factor activated by hypoxia, hyperglycemia, nitric oxide as well as ROS, suggesting a fundamental role in DPN susceptibility. We analyzed regulation of HIF1α in response to prolonged hyperglycemia. Genetically modified mutant mice, which conditionally lack HIF1α in peripheral sensory neurons (SNS-HIF1α), were analyzed longitudinally up to 6 months in the streptozotocin (STZ) model of type1 diabetes. Behavioral measurements of sensitivity to thermal and mechanical stimuli, quantitative morphological analyses of intraepidermal nerve fiber density, measurements of ROS, ROS-induced cyclic GMP-dependent protein kinase 1α (PKG1α), and levels of vascular endothelial growth factor (VEGF) in sensory neurons in vivo were undertaken over several months post-STZ injections to delineate the role of HIF1α in DPN. Longitudinal behavioral and morphological analyses at 5, 13, and 24 weeks post-STZ treatment revealed that SNS-HIF1α developed stronger hyperglycemia-evoked losses of peripheral nociceptive sensory axons associated with stronger losses of mechano- and heat sensation with a faster onset than HIF1α mice. Mechanistically, these histomorphologic, behavioral, and biochemical differences were associated with a significantly higher level of STZ-induced production of ROS and ROS-induced PKG1α dimerization in sensory neurons of SNS-HIF1α mice as compared with HIF1α. We found that prolonged hyperglycemia induced VEGF expression in the sciatic nerve which is impaired in SNS-HIF1α mice. Our results indicate that HIF1α is as an upstream modulator of ROS in peripheral sensory neurons and exerts a protective function in suppressing hyperglycemia-induced nerve damage by limiting ROS levels and by inducing expression of VEGF which may promote peripheral nerve survival. Our data suggested that HIF1α stabilization may be thus a new strategy target for limiting sensory loss, a debilitating late complication of diabetes. KEY MESSAGES: • Impaired hypoxia-inducible factor 1α (HIF1α) signaling leads to early onset of STZ-induced loss of sensation in mice. • STZ-induced loss of sensation in HIF1α mutant mice is associated with loss of sensory nerve fiber in skin. • Activation of HIF1α signaling in diabetic mice protects the sensory neurons by limiting ROS formation generated due to mitochondrial dysfunction and by inducing VEGF expression.
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http://dx.doi.org/10.1007/s00109-018-1707-9DOI Listing
December 2018

Peripheral Kappa Opioid Receptor Signaling Takes on a Central Role.

Neuron 2018 09;99(6):1102-1104

Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address:

With the current unmet demand for effective analgesics and the opioid crisis, pain relief without major central adverse effects is highly appealing. In this issue of Neuron, Snyder et al. (2018) report on the localization, functions, and therapeutic potential of kappa opioid receptors in peripheral sensory neurons.
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http://dx.doi.org/10.1016/j.neuron.2018.09.006DOI Listing
September 2018

A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity.

Nat Neurosci 2017 Nov 18;20(11):1591-1601. Epub 2017 Sep 18.

Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.

The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC-posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.
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http://dx.doi.org/10.1038/nn.4645DOI Listing
November 2017

Molecular, Cellular and Circuit Basis of Cholinergic Modulation of Pain.

Neuroscience 2018 09 8;387:135-148. Epub 2017 Sep 8.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Cell Networks Cluster of Excellence, Heidelberg University, Germany. Electronic address:

In addition to being a key component of the autonomic nervous system, acetylcholine acts as a prominent neurotransmitter and neuromodulator upon release from key groups of cholinergic projection neurons and interneurons distributed across the central nervous system. It has been more than forty years since it was discovered that cholinergic transmission profoundly modifies the perception of pain. Directly activating cholinergic receptors or extending the action of endogenous acetylcholine via pharmacological blockade of acetylcholine esterase reduces pain in rodents as well as humans; conversely, inhibition of muscarinic cholinergic receptors induces nociceptive hypersensitivity. Here, we aim to review the considerable progress in our understanding of peripheral, spinal and brain contributions to cholinergic modulation of pain. We discuss the distribution of cholinergic neurons, muscarinic and nicotinic receptors over the central nervous system and the synaptic and circuit-level modulation by cholinergic signaling. AchRs profoundly regulate nociceptive transmission at the level of the spinal cord via pre- as well as postsynaptic mechanisms. Moreover, we attempt to provide an overview of how some of the salient regions in the pain network spanning the brain, such as the primary somatosensory cortex, insular cortex, anterior cingulate cortex, the medial prefrontal cortex and descending modulatory systems are influenced by cholinergic modulation. Finally, we critically discuss the clinical relevance of cholinergic signaling to pain therapy. Cholinergic mechanisms contribute to several both conventional as well as unorthodox forms of pain treatments, and reciprocal interactions between cholinergic and opioidergic modulation impact on the function and efficacy of both opioids and cholinomimetic drugs.
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http://dx.doi.org/10.1016/j.neuroscience.2017.08.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150928PMC
September 2018

Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component.

Pain 2017 Nov;158(11):2243-2258

Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.

Neuropathic pain is an integral component of several chronic pain conditions and poses a major health problem worldwide. Despite emerging understanding of mechanisms behind neuropathic pain, the available treatment options are still limited in efficacy or associated with side effects, therefore making it necessary to find viable alternatives. In a genetic screen, we recently identified SerpinA3N, a serine protease inhibitor secreted in response to nerve damage by the dorsal root ganglion neurons and we showed that SerpinA3N acts against induction of neuropathic pain by inhibiting the T-cell- and neutrophil-derived protease, leucocyte elastase (LE). In the current study, via detailed in vivo pharmacology combined with analyses of evoked- and spontaneous pain-related behaviors in mice, we report that on systemic delivery, a single dose of 3 independent LE inhibitors can block established nociceptive hypersensitivity in early and late phases in the spared nerve injury model of traumatic neuropathic pain in mice. We further report the strong efficacy of systemic LE inhibitors in reversing ongoing pain in 2 other clinically relevant mouse models-painful diabetic neuropathy and cancer pain. Detailed immunohistochemical analyses on the peripheral tissue samples revealed that both T-Lymphocytes and neutrophils are the sources of LE on peripheral nerve injury, whereas neutrophils are the primary source of LE in diabetic neuropathic conditions. In summary, our results provide compelling evidence for a strong therapeutic potential of generic LE inhibitors for the treatment of neuropathic pain and other chronic pain conditions harboring a neuropathic pain component.
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http://dx.doi.org/10.1097/j.pain.0000000000001032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642338PMC
November 2017

Semaphorin 4C Plexin-B2 signaling in peripheral sensory neurons is pronociceptive in a model of inflammatory pain.

Nat Commun 2017 08 2;8(1):176. Epub 2017 Aug 2.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany.

Semaphorins and their transmembrane receptors, Plexins, are key regulators of axon guidance and development of neuronal connectivity. B-type Plexins respond to Class IV semaphorins and mediate a variety of developmental functions. Here we report that the expression of Plexin-B2 and its high-affinity ligand, Sema4C, persists in peripheral sensory neurons in adult life and is markedly increased in states of persistent pain in mice. Genetic deletion of Sema4C as well as adult-onset loss of Plexin-B2 leads to impairment of the development and duration of inflammatory hypersensitivity. Remarkably, unlike the neurodevelopmental functions of Plexin-B2 that solely rely on Ras signaling, we obtained genetic and pharmacological evidence for a requirement of RhoA-ROCK-dependent mechanisms as well as TRPA1 sensitization in pronociceptive functions of Sema4C-Plexin-B2 signaling in adult life. These results suggest important roles for Plexin-B2 signaling in sensory function that may be of therapeutic relevance in pathological pain.Semaphorins and their receptors are involved in neurodevelopment, but their functions in the adult nervous system are not fully understood. This study finds that semaphorin 4C and its receptor Plexin B are expressed in sensory neurons and are pronociceptive in a mouse model of inflammatory pain.
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http://dx.doi.org/10.1038/s41467-017-00341-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539317PMC
August 2017

A mouse model for pain and neuroplastic changes associated with pancreatic ductal adenocarcinoma.

Pain 2017 08;158(8):1609-1621

Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest human malignancies and is associated with excruciating pain, which is a serious complication and severely impacts the quality of life in patients. In human patients, poor survival prognosis is linked to remarkable remodeling of intrapancreatic nerves, which, in turn, is correlated to increased pain intensity. Understanding mechanisms underlying pain associated with PDAC has been hampered by the lack of animal models which replicate all germane aspects of the disease and importantly, enable analyses of pain associated with PDAC. In this study, we describe an immunocompetent orthotopic mouse model of PDAC involving intrapancreatic growth of K8484 mouse PDAC cells, which reliably exhibits a large number of key characteristics of human PDAC, including its unique histopathology and neuroplastic changes. We observed that tumor-bearing mice demonstrated significant abdominal mechanical hypersensitivity to von Frey stimuli as well as on-going pain in the conditioned place preference paradigm. Moreover, a myriad of other behavioral tests revealed that indicators of overall well-being were significantly reduced in tumor-bearing mice as compared to sham mice. Morphological and immunohistochemical analyses revealed structural remodeling in several different types of sensory and autonomic nerve fibers. Finally, perineural invasion of tumor cells, a cardinal manifestation in human PDAC, was also observed in our orthotopic mouse model. Thus, we describe a validated tumor model for quantitatively testing hypersensitivity and pain in PDAC, which lays a crucial basis for interrogating tumor-nerve interactions and the molecular and cellular mechanisms underlying pain in PDAC.
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http://dx.doi.org/10.1097/j.pain.0000000000000956DOI Listing
August 2017

Structural plasticity and reorganisation in chronic pain.

Nat Rev Neurosci 2017 01;18(2):113

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http://dx.doi.org/10.1038/nrn.2017.5DOI Listing
January 2017