Browsing by Subject "Hyperalgesia"

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    Changes in endocannabinoid signaling contribute to the anti-hyperalgesic effect of URB597 in a murine model of persistent inflammation.
    (2011-09) Lindberg, Amy Elizabeth
    Modulation of endocannabinoid neurotransmission has a therapeutic benefit in the treatment of inflammatory pain. Studies in this thesis investigated endocannabinoid signaling in a murine model of persistent, peripheral inflammation. Specifically, the ability of URB597, an inhibitor of fatty acid amide hydroxylase (FAAH), which degrades the endogenous cannabinoid anandamide, to reduce mechanical hyperalgesia associated with inflammation was determined. The first study tested whether local injection of URB597 dose-dependently reduced mechanical hyperalgesia associated with persistent inflammation. Inflammation was induced by injection of Complete Freund's Adjuvant (CFA) in the hind paw of mice and mechanical hyperalgesia was determined using a series of von Frey filaments. The first part of the study resolved that local injection of URB597 dose-dependently reduced mechanical hyperalgesia associated with persistent inflammation and decreased mechanical sensitivity in naïve mice. However, injection of URB597 did not result in increased endocannabinoid content in the plantar skin ipsilateral to the injection as would be expected based on the known mechanism of action of URB597. The second and third studies investigated the effect of inflammation on levels of FAAH, endocannabinoids and cannabinoid (CB)-1 receptor in naïve and CFA-injected mice to understand the neurochemistry underlying the anti-hyperalgesic effect of URB597. Levels FAAH mRNA decreased and enzyme activity trended toward a decrease in the plantar skin of the inflamed hind paw compared to tissue from naïve mice, but inflammation did not alter level of anandamide in plantar skin ipsilateral to the injections. In contrast, an increase in FAAH mRNA was accompanied by a decrease in the level of anandamide in dorsal root ganglia (DRGs) ipsilateral to the inflamed hind paw compared to naïve mice. In addition, there is an upregulation of functional CB1 receptors in DRGs ipsilateral to the inflamed hind paw in CFA-injected mice compared to DRGs from naïve mice. Together, these data support a model in which reduced synthesis of AEA in the primary afferent neurons may contribute to the mechanical hyperalgesia associated with peripheral inflammation, and upregulation of CB1 receptors on the primary afferent neurons affected by inflammation may be a compensatory response to decreased basal activation of AEA.
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    Role of Schwann cell-derived Exosomes in Cisplatin-induced Hyperalgesia
    (2018-05) Kim, Amy
    Painful peripheral neuropathy is a common dose-limiting side effect associated with cisplatin treatment. Cisplatin is unable to cross the blood-brain barrier, and its neurotoxicity is limited to the peripheral nervous system (PNS). In the PNS, Schwann cells are an essential component supporting dorsal root ganglion (DRG) neuron viability, and impairments in Schwann cell biology contribute to cisplatin-induced painful neuropathy. We explored the role of Schwann cell-derived exosomes in the development of cisplatin-induced hyperalgesia. Consistent with our previous reports, daily injection of cisplatin (1 mg/kg, i.p.) for 7 days produced mechanical hyperalgesia in C3H/HeN mice. To investigate the impact of exosome signaling in the development of cisplatin-induced hyperalgesia, exosomes isolated from the sciatic nerves of cisplatin-treated mice were injected intrathecally into naïve mice for 5 consecutive days (7 g of total protein/10 l, i.t.). Mechanical hyperalgesia was observed after the second injection of exosomes, mimicking the effect of cisplatin alone and supporting the involvement of integrated exosome signaling in hyperalgesia produced by cisplatin. Intrathecal administration of Schwann cell-derived exosomes activated microglia, and analysis of exosomal content indicated mediators of neuronal sensitization at the central level. Collectively, our results indicate that Schwann cells affected by cisplatin contribute to mechanical hyperalgesia and exosomes are an important signaling mediator for glia-neuronal communication.