2007). Increased glial activation is well known to occur in the dorsal horn of the spinal cord in animal models of peripheral neuropathy, as demonstrated by increased production
of glial fibriliary acidic protein (GFAP) in astrocytes and ionized calcium binding adaptor selleck chemicals molecule-1 (Iba-1) in microglia (Pekny and Pekna 2004; Racz et al. 2008b). When strongly activated, glia can increase expression of proinflammatory factors such as phosphorylated Inhibitors,research,lifescience,medical p38 mitogen-activated protein kinase (p-p38MAPK) that can lead to production and release of proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which subsequently bind and activate their respective receptors on nearby neurons and glia (De Leo et al. 2006; Watkins et al. 2007; Milligan Inhibitors,research,lifescience,medical and Watkins 2009). The cellular
anatomical localization of p-p38MAPK is predominantly expressed and is functionally important in spinal cord microglia and corresponding satellite cells in dorsal root ganglia (DRG) during neuropathic pain (Schafers et al. 2003; Svensson Inhibitors,research,lifescience,medical et al. 2005b; Boyle et al. 2006; Ji and Suter 2007; Sorkin et al. 2009). IL-1β mRNA and protein are upregulated within spinal cord homogenates of rats with pathological pain (Holguin et al. 2004). However, immunohistochemical detection of increased IL-1β protein, as well as alterations in the anti-inflammatory cytokine, interleukin-10 (IL-10), in intact spinal cord dorsal horn from rats with peripheral neuropathy has not yet been characterized. One goal of these studies is to quantify immunoreactivity Inhibitors,research,lifescience,medical (IR) for IL-1β as well as IL-10 in sections of the intact dorsal horn from rats with chronic peripheral neuropathy.
In addition, changes in immunoreactive p-p38MAPK levels Inhibitors,research,lifescience,medical were examined to verify prior reports that increase in p-p38MAPK occurs in combination with increased proinflammatory cytokine expression. Peripheral neuropathy is assessed by the presence of allodynia, characterized as a sensitivity to light mechanical touch that is not present under healthy conditions. AM1241 is a widely characterized cannabinoid agonist that controls hyperalgesia (exaggerated unless nociceptive thresholds) and allodynia following intraperitoneal (i.p.) (Ibrahim et al. 2006; Rahn et al. 2008), intravenous (i.v.) (Beltramo et al. 2006), intra-DRG, or intrathecal (i.t.) (Hsieh et al. 2011) injection. In the current studies, we sought to determine the timecourse and dose-dependent changes in allodynia produced by unilateral chronic constriction injury (CCI) of the rat sciatic nerve following i.t. AM1241 administration to avoid known peripheral actions of the compound. The development of bilateral allodynia following unilateral CCI has been documented in numerous studies (Paulson et al. 2000, 2002; Milligan et al. 2006, 2007; Loram et al. 2009).