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bioRxiv · 10.64898/2026.07.02.736158

Potential Role of Nociceptin/Orphanin FQ in the Progression of Multiple Sclerosis

Baker, J. C.·Paisley, C.·Poore, M.·Bigbee, J. W.·Oh, U.·Sato-Bigbee, C.
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Abstract

We showed before that the endogenous peptide Nociceptin blocks the premature differentiation of oligodendrocytes (OLGs), preventing untimely precocious myelination in the developing brain. Consistent with this early function, Nociceptin brain expression is developmentally regulated, sharply decreasing with the initiation and progression of myelination. However, we now found that at difference with controls and relapsing-remitting multiple sclerosis (RRMS), Nociceptin levels are highly elevated in cerebrospinal fluid from patients with the most severe progressive MS (PMS) forms. This questioned whether Nociceptin early developmental effects could be latter recapitulated, interfering with remyelination in PMS. This possibility was tested by inducing experimental autoimmune encephalomyelitis in older mice, at an age equivalent to that with increased risk of RRMS transition into PMS. Older animals develop persistently highly debilitating clinical symptoms, and display both brain and spinal cord demyelination. Importantly, these mice exhibit elevated brain Nociceptin levels, and their treatment with an antagonist of the Nociceptin receptor (NOR) elicits a regression of clinical scoring that is accompanied by higher ratios of OLGs/OLG progenitor cells, increased myelination, and reduction of reactive astrocytes. These findings suggest that Nociceptin may be a crucial player in the age-related progression of MS; interfering with OLG maturation and remyelination, and perhaps further exacerbating neurological dysfunction by targeting astrocyte populations. The upregulation of Nociceptin secretion by human astrocytes in response to proinflammatory cytokines, also points to this peptide as a mediator of microglia-astrocyte interactions supporting MS progression with aging. NOR may offer a novel pharmacological target for ameliorating the devastating effects of MS progression.

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Baker, J. C., Paisley, C., Poore, M., Bigbee, J. W., Oh, U., Sato-Bigbee, C.. 2026-07-08. Potential Role of Nociceptin/Orphanin FQ in the Progression of Multiple Sclerosis. https://doi.org/10.64898/2026.07.02.736158

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