Transient receptor potential channels: Emerging roles in health and disease

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 (200 μg) and adjuvants comprising Quil A (45 μg) and pertussis toxin (2 × 250 ng). 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 28–30 days post-immunization (p.i.) and was maintained until study completion (52–60 days p.i.), in the absence of confounding motor deficits. Single bolus doses of amitriptyline (1–7 mg/kg), gabapentin (10–50 mg/kg) and morphine (0.1–2 mg/kg) evoked dose-dependent analgesia in the bilateral hindpaws of EAE-mice; the corresponding ED50s were 1.5, 20 and 1 mg/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.