Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice.

The chronic administration of morphine and related opioid drugs results in tolerance and dependence which reduces the clinical utility of these agents. The CO/NO-cGMP signal transduction cascade plays an important role in morphine tolerance. Principal components of this pathway include heme oxygenase (HO), nitric oxide synthase (NOS), soluble guanylate cyclase (sGC) and cyclic GMP-dependent protein kinase (cGK). We measured and compared the spinal gene expression patterns of these key components using real-time PCR and Western blot analysis after chronic morphine treatment in mice. Our findings indicate that the CO/NO-cGMP signaling pathway is upregulated at multiple points after morphine exposure demonstrating a coordinated molecular and biochemical response. These findings underscore the importance of this signaling pathway in the neuroplastic events occurring during chronic opioid exposure and the value of analyzing the participation of multiple components of a signaling pathway simultaneously rather than individual members in isolation.