title: Establishment and characterization of an optimized mouse model of multiple sclerosis-induced neuropathic pain using behavioral, pharmacologic, histologic and immunohistochemical methods.
abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes debilitating central neuropathic pain in many patients. Although mouse models of experimental autoimmune encephalomyelitis (EAE) have provided insight on the pathobiology of MS-induced neuropathic pain, concurrent severe motor impairments confound quantitative assessment of pain behaviors over the disease course. To address this issue, we have established and characterized an optimized EAE-mouse model of MS-induced neuropathic pain. Briefly, C57BL/6 mice were immunized with MOG35-55 (200μg) and adjuvants comprising Quil A (45μg) and pertussis toxin (2×250ng). The traditionally used Freund's Complete Adjuvant (FCA) was replaced with Quil A, as FCA itself induces CNS neuroinflammation. Herein, EAE-mice exhibited a mild relapsing-remitting clinical disease course with temporal development of mechanical allodynia in the bilateral hindpaws. Mechanical allodynia was fully developed by 28-30days post-immunization (p.i.) and was maintained until study completion (52-60days p.i.), in the absence of confounding motor deficits. Single bolus doses of amitriptyline (1-7mg/kg), gabapentin (10-50mg/kg) and morphine (0.1-2mg/kg) evoked dose-dependent analgesia in the bilateral hindpaws of EAE-mice; the corresponding ED50s were 1.5, 20 and 1mg/kg respectively. At day 39 p.i. in EAE-mice exhibiting mechanical allodynia in the hindpaws, there was marked demyelination and gliosis in the brain and lumbar spinal cord, mirroring these pathobiologic hallmark features of MS in humans. Our optimized EAE-mouse model of MS-associated neuropathic pain will be invaluable for future investigation of the pathobiology of MS-induced neuropathic pain and for efficacy profiling of novel molecules as potential new analgesics for improved relief of this condition.
authors.affiliation: The University of Queensland, Center for Integrated Preclinical Drug Development, St Lucia Campus, Brisbane, Queensland 4072, Australia; School of Pharmacy, The University of Queensland, Pharmacy Australia Center of Excellence, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Nemat
authors.initials: N
authors.lastname: Khan
authors.affiliation: The School of Biomedical Sciences, University of Queensland, St Lucia Campus, Brisbane, Queensland 4072, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: The University of Queensland, Center for Integrated Preclinical Drug Development, St Lucia Campus, Brisbane, Queensland 4072, Australia; School of Pharmacy, The University of Queensland, Pharmacy Australia Center of Excellence, Woolloongabba, Brisbane, Queensland 4102, Australia. Electronic address: maree.smith@uq.edu.au.
authors.forename: Maree T
authors.initials: MT
authors.lastname: Smith
mesh_terms: D000588:Amines / Q000627:therapeutic use*; D000639:Amitriptyline / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001921:Brain / Q000473:pathology; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D003711:Demyelinating Diseases / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D005260:Female; D000077206:Gabapentin; D005684:Gait; D005911:Gliosis / Q000473:pathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D051379:Mice; D009020:Morphine / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy*; D010446:Peptide Fragments; D037342:Pertussis Toxin; D062605:Quillaja Saponins; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: D000588:Amines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003509:Cyclohexanecarboxylic Acids; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D062605:Quillaja Saponins; C526792:myelin oligodendrocyte glycoprotein (35-50), Ala(37)-; D000639:Amitriptyline; D005680:gamma-Aminobutyric Acid; C046386:Quil A; D000077206:Gabapentin; D009020:Morphine; D037342:Pertussis Toxin
keywords: Analgesia; Experimental autoimmune encephalomyelitis (EAE); Mechanical allodynia; Multiple sclerosis (MS); Neuroinflammation; Neuropathic pain