6 research outputs found
Nicotine dependence produces hyperalgesia: Role of corticotropin-releasing factor-1 receptors (CRF1Rs) in the central amygdala (CeA)
Because tobacco use has a large negative health and financial impact on society, it is critical to identify
the factors that drive excessive use. These factors include the aversive withdrawal symptoms that
manifest upon cessation of tobacco use, and may include increases in nociceptive processing.
Corticotropin-releasing factor (CRF) signalling in the central amygdala (CeA) has been attributed an
important role in: (1) central processing of pain, (2) excessive nicotine use that results in nicotine
dependence, and (3) in mediating the aversive symptoms that manifest following cessation of tobacco
exposure. Here, we describe three experiments in which the main hypothesis was that CRF/CRF1 receptor
(CRF1R) signalling in the CeA mediates nicotine withdrawal-induced increases in nociceptive sensitivity
in rats that are dependent on nicotine. In Experiment 1, nicotine-dependent rats withdrawn from chronic
intermittent (14-h/day) nicotine vapor exhibited decreased hind paw withdrawal latencies in response to
a painful thermal stimulus in the Hargreaves test, and this effect was attenuated by systemic administration
of the CRF1R antagonist, R121919. In Experiment 2, nicotine-dependent rats withdrawn from
nicotine vapor exhibited robust increases in mRNA for CRF and CRF1Rs in CeA. In Experiment 3, intra-CeA
administration of R121919 reduced thermal nociception only in nicotine-dependent rats. Collectively,
these results suggest that nicotine dependence increases CRF/CRF1R signaling in the CeA that mediates
withdrawal-induced increases in sensitivity to a painful stimulus. Future studies will build on these
findings by exploring the hypothesis that nicotine withdrawal-induced reduction in pain thresholds
drive excessive nicotine use via CRF/CRF1R signalling pathways
Muscle stem cells and fibro-adipogenic progenitors in female pelvic floor muscle regeneration following birth injury
Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs), supported by the fibro-adipogenic progenitors (FAPs) and immune cells, are indispensable for the regeneration of injured appendicular skeletal muscles. However, almost nothing is known about their role in PFM regeneration following birth injury. To elucidate the role of MuSCs, FAPs, and immune infiltrate in this context, we used radiation to perturb cell function and followed PFM recovery in a validated simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7,10, and 28 days post-SBI (dpi). Twenty-eight dpi, PFM fiber cross-sectional area (CSA) was significantly lower and the extracellular space occupied by immune infiltrate was larger in irradiated relative to nonirradiated injured animals. Following SBI in non-irradiated animals, MuSCs and FAPs expanded significantly at 7 and 3 dpi, respectively; this expansion did not occur in irradiated animals at the same time points. At 7 and 10 dpi, we observed persistent immune response in PFMs subjected to irradiation compared to non-irradiated injured PFMs. CSA of newly regenerated fibers was also significantly smaller following SBI in irradiated compared to non-irradiated injured PFMs. Our results demonstrate that the loss of function and decreased expansion of MuSCs and FAPs after birth injury lead to impaired PFM recovery. These findings form the basis for further studies focused on the identification of novel therapeutic targets to counteract postpartum PFM dysfunction and the associated pelvic floor disorders