Abstract
Neuropathic pain is a chronic symptom of multiple sclerosis (MS) and affects nearly half of all MS sufferers. A key instigator of this pain is the pro-inflammatory response in MS. We investigated the behavioral effects of immunization with a mutant peptide of myelin basic protein (MBP), termed altered peptide ligand (APL), known to initiate immune deviation from a pro-inflammatory state to an anti-inflammatory response in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male and female Lewis rats were injected with vehicle control or with varying doses of 50 or 100 μg guinea pig MBP in combination with or without APL. APL-treated animals established significantly lower disease severity compared to encephalitogenic MBP-treated animals. Animals with EAE developed mechanical, but not thermal pain hypersensitivity. Mechanical pain sensitivities were either improved or normalized during periods of clinical disease in male and female APL-treated animals as compared to the encephalitogenic group. No significant changes to thermal latency were observed upon co-immunization with APL. Together these data indicate that APL ameliorates disease states and selectively mediates an analgesic effect on EAE animals.
Highlights
Multiple sclerosis (MS) is a chronic, T cell-mediated autoimmune neurological disease of the central nervous system (CNS) [1, 2], characterized by the production of acute multifocal CNS lesions with concurrent perivenular inflammation, demyelination, neuronal degeneration, and gliosis in gray and white matter [3, 4]
EFFECTS OF CO-IMMUNIZATION WITH altered peptide ligand (APL), CYCLO-(87–99)[A91,A96]MBP87–99, IN MALE LEWIS RATS INJECTED WITH 100 μg gp-myelin basic protein (MBP) We first studied the effects of APL vaccination on EAE clinical disease course and changes to mechanical threshold and thermal latency for pain in 18 male Lewis rats immunized with 100 μg guinea pig MBP (gp-MBP)
Three study groups were used, (i) animals injected with CFA only, (ii) animals injected with CFA + 100 μg gp-MBP (MBP group) and, (iii) animals co-immunized with CFA + 100 μg gp-MBP + 250 μg cyclo-(87– 99)[A91,A96]MBP87–99 (APL group)
Summary
Multiple sclerosis (MS) is a chronic, T cell-mediated autoimmune neurological disease of the central nervous system (CNS) [1, 2], characterized by the production of acute multifocal CNS lesions with concurrent perivenular inflammation, demyelination, neuronal degeneration, and gliosis in gray and white matter [3, 4]. While the cause of the disease is not known, pro-inflammatory CD4+ T cells, CD8+ T cells, B cells, macrophages, and natural killer cells have been implicated in disease onset and progression [4, 5]. It results from damage to the nervous system [11], and presents in various forms such as ongoing extremity pain, paroxysmal neuropathic pain (e.g., trigeminal neuralgia, Lhermitte’s phenomenon), hyperalgesia (increased sensitivity to pain), and allodynia (pain produced by innocuous stimuli) [8, 12,13,14]. While the mechanisms underlying MS-related neuropathic pain are not fully understood, lesions of CNS areas associated with pain, activation of T lymphocytes, and pro-inflammatory responses have been shown to contribute to the development and maintenance of neuropathic pain [15,16,17]
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