Yue, W. W. S. | bioRxiv Science

bioRxiv2023

Endogenous Opioid Signaling Regulates Proliferation of Spinal Cord Ependymal Cells

After injury, mammalian spinal cords develop scars to seal off the damaged area and prevent further injury. However, excessive scarring can hinder neural regeneration and functional recovery (1, 2). These competing actions underscore the importance of developing therapeutic strategies to dynamically modulate the extent of scar formation. Previous research on scar formation has primarily focused on the role of astrocytes, but recent evidence suggests that ependymal cells also participate. Ependymal cells normally form the epithelial layer encasing the central canal, but they undergo massive proliferation and differentiation into astroglia following certain types of injury, becoming a core component of scars (3-7). However, the mechanisms regulating ependymal proliferation in vivo in both healthy and injured conditions remain unclear. Here, we uncover an intercellular kappa ({kappa}) opioid signaling pathway that controls endogenous ependymal proliferation. Specifically, we detect expression of the {kappa} opioid receptor, OPRK1, in a functionally under-characterized cell type called cerebrospinal fluid-contacting neurons (CSF-cNs). We also discover a neighboring cell population that express the cognate ligand, prodynorphin (PDYN). Importantly, OPRK1 activation excites CSF-cNs, and systemic administration of a {kappa} antagonist enhances ependymal proliferation in uninjured spinal cords in a CSF-cN-dependent manner. Moreover, injecting a {kappa} agonist reduces the proliferation induced by dorsal hemisection. Altogether, our data suggest a regulatory mechanism whereby PDYN+ cells tonically release {kappa} opioids to stimulate CSF-cNs, which in turn suppress ependymal proliferation. This endogenous pathway provides a mechanistic basis for the potential use of {kappa} opiates in modulating scar formation and treating spinal cord injuries.

neuroscience↗

bioRxiv2022

TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons

TRPV1, a capsaicin- and heat-sensitive ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, their utility is limited because TRPV1 agonists and antagonists thus far examined show thermo-modulatory side effects in animal models and human clinical trials. These on-target effects may result from the perturbation of TRPV1 receptors on nociceptors, which transduce signals to central thermoregulatory circuits and also release pro-inflammatory factors from their peripheral terminals, such as the vasodilative neuropeptide calcitonin gene-related peptide (CGRP). Alternatively, they may originate from the modulation of TRPV1 on vascular smooth muscle cells (vSMCs), where channel activation promotes arteriole constriction. Here, we ask which of these pathways is most responsible for the body temperature perturbations elicited by TRPV1 drugs in vivo. We address this question by selectively eliminating TRPV1 expression in sensory neurons or vSMCs and show that only the former abrogates agonist-induced hypothermia and antagonist-induced hyperthermia. Furthermore, lesioning the central projections of TRPV1-positive sensory nerve fibers also abrogates drug-mediated thermo-modulation, whereas eliminating CGRP has no effect. Thus, TRPV1 drugs alter core body temperature by modulating sensory input to the central nervous system, rather than through peripheral actions on the vasculature. These findings suggest how mechanically distinct TRPV1 antagonists may diminish inflammatory pain without affecting core body temperature.

physiology↗