Owing to the primary source of iNOS, mRNA and protein expression in the inflammed tissue is usually activated in resident immune cells and immune cells that traffic to sites of inflammation from your systemic circulation; then, these cell populace could contribute to the increased iNOS gene expression reported in our study (Kalff et al., 2000). inflammation from your systemic circulation; then, these cell populace could contribute to the increased iNOS gene expression reported in our study (Kalff et al., 2000). In summary, our results show that the increased gastrointestinal transit induced by croton oil appears to be mediated by nitric oxide derived from iNOS since: (1) the inducible form of NOS is usually increased during croton oil-induced inflammation, (2) the specific inhibitor of the enzyme normalizes transit and (3) gastrointestinal transit is not altered in iNOS?/? deficient mice treated with croton oil. The role of nitric oxide around the enhanced intestinal effects of -opioids during inflammation was evaluated by measuring the antitransit effects of morphine (MOR agonist) in animals treated with NOS inhibitors. According to previous studies, the antitransit effects of morphine were significantly increased during intestinal inflammation (Puig & Pol, 1998). However, this increased potency of morphine (9.5 occasions) was significantly diminished in iNOS?/? mice and in RO9021 WT mice treated with RO9021 L-NAME or L-NIL. In control animals, the administration of NOS inhibitors did not alter RO9021 the antitransit effects of morphine. Thus, nitric oxide appears to mediate the enhanced effects of -opioids during peripheral inflammation. The fact that treatment with a specific (L-NIL) or the nonspecific NOS inhibitor (L-NAME) produced similar effects suggests that nitric oxide synthesized by Rabbit Polyclonal to OR5B3 iNOS could be primarily responsible for the observed effects. This hypothesis is usually supported by the 10-fold increase in the iNOS mRNA levels in the gut of WT mice with intestinal inflammation. Other inflammatory brokers such as indomethacin and TNBS, also increase iNOS mRNA levels (Evans et al., 2000; Yue et al, 2001). This is the first study to report that this nitric oxide pathway is usually involved in the antitransit effects of morphine during intestinal inflammation. Our results agree with data reported in other nociceptive models of peripheral inflammation in which the analgesic effects of -opioids were enhanced or diminished by the local administration of nitric oxide donors or NOS inhibitors, respectively (Nozaki-Taguchi & Yamamoto, 1998; Tasatargil & Sadan, 2004). Granados-Soto et al. (1997) also exhibited that peripheral administration of methylene blue (a soluble guanylyl cyclase inhibitor) significantly attenuated the antinociceptive effects of morphine, supporting the view that this activated L-arginine/nitric oxide/cGMP pathway during inflammation is usually implicated in the antinociceptive effects produced RO9021 by -opioids in this experimental condition. In this work, intestinal inflammation induced by croton oil was confirmed RO9021 by the measurement of MPO activity (3.5-fold increase) and according to other inflammatory models (Kolios et al., 2004), the administration of a non-(L-NAME) and a specific iNOS inhibitor (L-NIL), both attenuated the intestinal inflammation induced by croton oil. Since the increased potency of morphine in croton oil-treated animals was also diminished after L-NAME or L-NIL treatment, a significant correlation between the levels of intestinal inflammation and the morphine antitransit effects in animals treated with and without NOS inhibitors has been exhibited. We and other investigators have shown that intestinal inflammation enhances the transcription and expression of MOR in the gut, thus explaining the increased antitransit and also the anti-inflammatory effects induced by -opioids during intestinal inflammation (Pol et al., 2001; Philippe et al., 2003). Similarly, the analgesic effects of -opioids were also augmented in animals with peripheral inflammation related to an upregulation of peripheral MOR (mRNA and proteins) that occurs under inflammatory conditions (Z?llner et al., 2003; Puehler et al., 2004). In croton oil-treated animals, the augmented effect of morphine was exhibited by an increase.