Browsing by Author "Abdullah, Nasser Salem"

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    Early Life Regulation of TRPV1+ Nociceptors by the Microbiome: Implications for Pathological Pain?
    (2024-04-30) Abdullah, Nasser Salem; Altier, Christophe; Trang, Tuan; Hirota, Simon
    Pain is essential for the survival and wellbeing of organisms. Dysregulation in the pain pathway leads to pathological pain in part due to poor pain management stemming from a lack of understanding of the underlying mechanisms that lead to pathological pain. Pain is initiated by specialised primary afferent neurons called nociceptors. TRPV1+ nociceptors play a central role in multiple pathological pain conditions, including inflammatory pain, where their sensitization can lead to chronic pain. In this thesis, we shed light on how TRPV1+ nociceptors participate in chronic pain and the factors that contribute to their regulation. This thesis provides two studies divided into 3 chapters. The first study (Chapter 3) is focused on the role of TRPV1+ nociceptors in initiating chronic visceral pain. The second study (Chapter 4 and 5) is focused on understanding how the early life microbiome regulates the sensitivity of TRPV1+ nociceptors. In Chapter 3, we present findings indicating that in a murine model of colitis, TRPV1+ nociceptors activate spinal microglia leading to visceral hypersensitivity, demonstrating their essential role for the transition from acute to chronic pain in the context of colitis. In Chapter 4, we investigated the role of the early life microbiome on TRPV1+ nociceptor specification and pain sensitivity using germ-free mice and then germ-free mice colonized before or after weaning. We found that a lack of microbiome in early life leads to hyposensitivity to heat and capsaicin, The hyposensitive phenotype was not due to changes in nociceptor specification, innervation, or TRPV1 expression, but it correlated with a reduction in TRPV1 trafficking to the cell membrane. In Chapter 5, we investigated the underlying mechanisms for early life microbiome induced hyposensitivity and identified that the early life microbiome regulates the sensitivity of nociceptors and the trafficking of TRPV1 through regulating mast cell derived NGF. Altogether, this study demonstrates the central role of TRPV1+ nociceptors in inducing the transition to chronic pain and the important role of the early life microbiome in regulating the sensitivity of these nociceptors through mast cell derived NGF.