Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

Neuropathic pain pathophysiology is not fully understood, but it was recently shown that MIP-1 family members (CCL3, CCL4, and CCL9) have strong pronociceptive properties. Our goal was to examine how pharmacological modulation of these chemokines and their receptors (CCR1 and CCR5) influence hypersensitivity after nerve injury in Albino Swiss male mice. The spinal changes in the mRNA/protein levels of the abovementioned chemokines and their receptors were measured using RT-qPCR and ELISA/Western blot techniques in a mouse model of chronic constriction injury of the sciatic nerve. Behavioral studies were performed using the von Frey and cold plate tests after pharmacological treatment with neutralizing antibodies (nAbs) against chemokines or antagonists (CCR1-J113863, CCR5-TAK-220/AZD-5672) alone and in coadministration with morphine on Day 7, when the hypersensitivity was fully developed. Our results showed enhanced protein levels of CCL3 and CCL9 1 and 7 days after nerve injury. The single intrathecal administration of CCL3 or CCL9 nAb, J113863, TAK-220, or AZD-5672 diminished neuropathic pain symptoms and enhanced morphine analgesia. These findings highlight the important roles of CCL3 and CCL9 in neuropathic pain and additionally indicate that these chemokines play essential roles in opioid analgesia. The obtained results suggest CCR1 and CCR5 as new, interesting targets in neuropathy treatment.

[1]  K. Kwiatkowski,et al.  Pharmacological Evidence of the Important Roles of CCR1 and CCR3 and Their Endogenous Ligands CCL2/7/8 in Hypersensitivity Based on a Murine Model of Neuropathic Pain , 2022, Cells.

[2]  A. Piotrowska,et al.  New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies , 2022, Frontiers in Immunology.

[3]  Marion Gaborit,et al.  Therapeutic potential of opioid receptor heteromers in chronic pain and associated comorbidities , 2021, British journal of pharmacology.

[4]  E. Rojewska,et al.  Blockade of CC Chemokine Receptor Type 3 Diminishes Pain and Enhances Opioid Analgesic Potency in a Model of Neuropathic Pain , 2021, Frontiers in Immunology.

[5]  J. Barrett,et al.  Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression. , 2021, Life sciences.

[6]  A. Piotrowska,et al.  Comparison of the Effects of Chemokine Receptors CXCR2 and CXCR3 Pharmacological Modulation in Neuropathic Pain Model—In Vivo and In Vitro Study , 2021, International journal of molecular sciences.

[7]  S. Videla Cés,et al.  Combination Therapy for Neuropathic Pain: A Review of Recent Evidence , 2021, Journal of clinical medicine.

[8]  J. Dobrogowski,et al.  CCR4 Antagonist (C021) Administration Diminishes Hypersensitivity and Enhances the Analgesic Potency of Morphine and Buprenorphine in a Mouse Model of Neuropathic Pain , 2020, Frontiers in Immunology.

[9]  F. W. Albert,et al.  Simultaneous quantification of mRNA and protein in single cells reveals post-transcriptional effects of genetic variation , 2020, bioRxiv.

[10]  T. Jensen,et al.  Neuropathic pain: From mechanisms to treatment. , 2020, Physiological reviews.

[11]  J. Dobrogowski,et al.  Blockade of CCR4 Diminishes Hypersensitivity and Enhances Opioid Analgesia – Evidence from a Mouse Model of Diabetic Neuropathy , 2020, Neuroscience.

[12]  K. Kwiatkowski,et al.  Comparison of the beneficial effects of RS504393, maraviroc and cenicriviroc on neuropathic pain-related symptoms in rodents: behavioral and biochemical analyses. , 2020, International immunopharmacology.

[13]  M. Oggioni,et al.  Changes in macrophage inflammatory protein-1 (MIP-1) family members expression induced by traumatic brain injury in mice. , 2020, Immunobiology.

[14]  T. Rogers.  Bidirectional Regulation of Opioid and Chemokine Function , 2020, Frontiers in Immunology.

[15]  A. Piotrowska,et al.  The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain , 2020, Immunology.

[16]  T. Eisenstein,et al.  Chemokine Receptor Antagonists in Combination with Morphine as a Novel Strategy for Opioid Dose Reduction in Pain Management. , 2020, Military medicine.

[17]  T. Yaksh,et al.  Neuraxial Cytokines in Pain States , 2020, Frontiers in Immunology.

[18]  A. Piotrowska,et al.  Pharmacological Blockade of Spinal CXCL3/CXCR2 Signaling by NVP CXCR2 20, a Selective CXCR2 Antagonist, Reduces Neuropathic Pain Following Peripheral Nerve Injury , 2019, Front. Immunol..

[19]  M. Nedergaard,et al.  Astrocytes in chronic pain and itch , 2019, Nature Reviews Neuroscience.

[20]  A. Piotrowska,et al.  Chemokines CCL2 and CCL7, but not CCL12, play a significant role in the development of pain-related behavior and opioid-induced analgesia. , 2019, Cytokine.

[21]  S. Carmichael,et al.  CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury , 2019, Cell.

[22]  A. Piotrowska,et al.  Pharmacological blockade of CXCR3 by (±)-NBI-74330 reduces neuropathic pain and enhances opioid effectiveness - Evidence from in vivo and in vitro studies. , 2018, Biochimica et biophysica acta. Molecular basis of disease.

[23]  T. Eisenstein,et al.  Coadministration of Chemokine Receptor Antagonists with Morphine Potentiates Morphine’s Analgesic Effect on Incisional Pain in Rats , 2018, The Journal of Pharmacology and Experimental Therapeutics.

[24]  K. Kwiatkowski,et al.  The importance of chemokines in neuropathic pain development and opioid analgesic potency , 2018, Pharmacological reports : PR.

[25]  A. Piotrowska,et al.  Involvement of Macrophage Inflammatory Protein-1 Family Members in the Development of Diabetic Neuropathy and Their Contribution to Effectiveness of Morphine , 2018, Front. Immunol..

[26]  D. Fornasari.  Pharmacotherapy for Neuropathic Pain: A Review , 2017, Pain and Therapy.

[27]  A. Piotrowska,et al.  Spinal CCL1/CCR8 signaling interplay as a potential therapeutic target – Evidence from a mouse diabetic neuropathy model , 2017, International immunopharmacology.

[28]  A. Larsson,et al.  High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls , 2017, Pain.

[29]  Simon C Watkins,et al.  C‐C Chemokine Receptor Type 5 (CCR5)‐Mediated Docking of Transferred Tregs Protects Against Early Blood‐Brain Barrier Disruption After Stroke , 2017, Journal of the American Heart Association.

[30]  A. Piotrowska,et al.  The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats , 2017, Journal of Neuroimmune Pharmacology.

[31]  R. Freeman,et al.  Neuropathic pain , 1999, The Lancet.

[32]  S. Herculano‐Houzel,et al.  The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting , 2016, The Journal of comparative neurology.

[33]  D. Selley,et al.  Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization. , 2016, Bioorganic & medicinal chemistry.

[34]  Lengchen Hou,et al.  Role of interleukin-4, the chemokine CCL3 and its receptor CCR5 in neuropathic pain. , 2016, Molecular immunology.

[35]  A. Piotrowska,et al.  Maraviroc reduces neuropathic pain through polarization of microglia and astroglia – Evidence from in vivo and in vitro studies , 2016, Neuropharmacology.

[36]  A. Piotrowska,et al.  Microglial Inhibition Influences XCL1/XCR1 Expression and Causes Analgesic Effects in a Mouse Model of Diabetic Neuropathy , 2016, Anesthesiology.

[37]  M. Fernández-García,et al.  Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice , 2016, Basic & clinical pharmacology & toxicology.

[38]  A. Basta-Kaim,et al.  Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats , 2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[39]  B. Ryffel,et al.  Spinal cord oligodendrocyte‐derived alarmin IL‐33 mediates neuropathic pain , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  Emily Battinelli,et al.  Cytokine-specific Neurograms in the Sensory Vagus Nerve , 2016, Bioelectronic medicine.

[41]  F. Knerlich-Lukoschus.  Chemokines and their receptors: important mediators to be aware of in neuroregenerative approaches for spinal cord injury , 2015, Neural regeneration research.

[42]  Meiping Zhu,et al.  Neuroinflammation in Alzheimer's disease: chemokines produced by astrocytes and chemokine receptors. , 2014, International journal of clinical and experimental pathology.

[43]  K. Biber,et al.  Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain , 2014, Front. Cell. Neurosci..

[44]  T. Maeda,et al.  CCL3 Production by Microglial Cells Modulates Disease Severity in Murine Models of Retinal Degeneration , 2014, The Journal of Immunology.

[45]  Blair H. Smith,et al.  Neuropathic pain in the general population: A systematic review of epidemiological studies , 2014, PAIN®.

[46]  Martin J. Lohse,et al.  G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives , 2014, Pharmacological Reviews.

[47]  F. Gao,et al.  Activation of CXCL10/CXCR3 Signaling Attenuates Morphine Analgesia: Involvement of Gi Protein , 2014, Journal of Molecular Neuroscience.

[48]  B. Przewłocka,et al.  Importance of glial activation in neuropathic pain. , 2013, European journal of pharmacology.

[49]  R. Koenen,et al.  Exchange of extracellular domains of CCR1 and CCR5 reveals confined functions in CCL5-mediated cell recruitment , 2013, Thrombosis and Haemostasis.

[50]  D. Bennett,et al.  Neuroinflammation and the generation of neuropathic pain. , 2013, British journal of anaesthesia.

[51]  Fen Hu,et al.  Spinal MCP-1 Contributes to the Development of Morphine Antinociceptive Tolerance in Rats , 2012, The American journal of the medical sciences.

[52]  N. Kiguchi,et al.  CC‐chemokine ligand 4/macrophage inflammatory protein‐1β participates in the induction of neuropathic pain after peripheral nerve injury , 2012, European journal of pain.

[53]  A. Pittaluga,et al.  RANTES‐mediated control of excitatory amino acid release in mouse spinal cord , 2012, Journal of neurochemistry.

[54]  John Williams,et al.  Basic opioid pharmacology: an update , 2012, British journal of pain.

[55]  M. Parat,et al.  Morphine Use in Cancer Surgery , 2011, Front. Pharmacol..

[56]  G. Bardi,et al.  Protein Kinase Cζ Mediates μ-Opioid Receptor-induced Cross-desensitization of Chemokine Receptor CCR5* , 2011, The Journal of Biological Chemistry.

[57]  K. Lukasiuk,et al.  Status epilepticus evokes prolonged increase in the expression of CCL3 and CCL4 mRNA and protein in the rat brain. , 2011, Acta neurobiologiae experimentalis.

[58]  R. Ji,et al.  Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. , 2010, Pharmacology & therapeutics.

[59]  N. Shehadeh,et al.  Selective Autoantibody Production against CCL3 Is Associated with Human Type 1 Diabetes Mellitus and Serves As a Novel Biomarker for Its Diagnosis1 , 2009, The Journal of Immunology.

[60]  A. Kataoka,et al.  Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT , 2009, Journal of neurochemistry.

[61]  K. Westlund,et al.  Plasticity in intact Aδ- and C-fibers contributes to cold hypersensitivity in neuropathic rats , 2007, Neuroscience.

[62]  H. Lassmann,et al.  Temporal expression and cellular origin of CC chemokine receptors CCR1, CCR2 and CCR5 in the central nervous system: insight into mechanisms of MOG-induced EAE , 2007, Journal of Neuroinflammation.

[63]  M. Adler,et al.  Rapid heterologous desensitization of antinociceptive activity between mu or delta opioid receptors and chemokine receptors in rats. , 2007, Drug and alcohol dependence.

[64]  R. Ransohoff,et al.  The many roles of chemokines and chemokine receptors in inflammation. , 2006, The New England journal of medicine.

[65]  M. Caterina,et al.  A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[66]  S. Maier,et al.  Behavioral/systems/cognitive a Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine , 2022 .

[67]  M. Caterina,et al.  Proinflammatory Chemokines, Such as C-C Chemokine Ligand 3, Desensitize μ-Opioid Receptors on Dorsal Root Ganglia Neurons1 , 2004, The Journal of Immunology.

[68]  Chongguang Chen,et al.  Heterodimerization and cross-desensitization between the mu-opioid receptor and the chemokine CCR5 receptor. , 2004, European journal of pharmacology.

[69]  Chongguang Chen,et al.  Selective inactivation of CCR5 and decreased infectivity of R5 HIV‐1 strains mediated by opioid‐induced heterologous desensitization , 2003, Journal of leukocyte biology.

[70]  Mario Saltarelli,et al.  Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. , 2003, Archives of neurology.

[71]  R. Doi,et al.  Interactions of opioid and chemokine receptors: oligomerization of mu, kappa, and delta with CCR5 on immune cells. , 2002, Experimental cell research.

[72]  M. Adler,et al.  Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[73]  Haiyan Xu,et al.  Hypoxic-Ischemic Injury Induces Macrophage Inflammatory Protein-1&agr; Expression in Immature Rat Brain , 2002, Stroke.

[74]  J. Eisenach,et al.  Pharmacology of opioid and nonopioid analgesics in chronic pain states. , 2001, The Journal of pharmacology and experimental therapeutics.

[75]  B. Hyman,et al.  Immunohistochemical Study of the β-Chemokine Receptors CCR3 and CCR5 and Their Ligands in Normal and Alzheimer's Disease Brains , 1998 .

[76]  J. Newcombe,et al.  Expression of monocyte chemoattractant protein-1 and other β-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions , 1998, Journal of Neuroimmunology.

[77]  C. Mackay,et al.  Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. , 1997, The American journal of pathology.

[78]  Gary J. Bennett,et al.  A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man , 1988, Pain.

[79]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.