, 2000), Grace et al. (2001) reported that subcutaneous injection of NSAIDs completely eliminated the hyperalgesic response elicited in rats by ischemic stimulation of the tail and suppressed the increased prostaglandin formation in the brains of the animals. However, the relief of hyperalgesia was short-lived and corresponded only to the first phase of the (spontaneous) hyperalgesia ( Scheuren et al., 1997). In addition, PGE2 has been found in microdialysate of the spinal cord after

injection of formalin in the paw of the rat ( Malmberg and Yaksh, 1995 and Scheuren et al., 1997), MK-8776 mw and its production was antagonized by systemic injection of paracetamol ( Muth-Selbach et al., 1999) or by intrathecal injection of other NSAIDs ( Malmberg and Yaksh, 1992). Direct evidence for a spinal antinociceptive action of NSAIDs derives from observations made in patients and animal experiments. It has been reported that intrathecal injection of acetylsalicylic acid, salicylic acid, and indomethacin depressed the nociceptive activity that was evoked in thalamic neurons of rats by electrical stimulation of afferent C-type fibers in the sural nerve ( Jurna et al., 1992). The development of nociceptive pathways is an activity-dependent process (Fitzgerald and Jennings, 1999, Fitzgerald and Beggs, 2001 and Beggs et al., 2002), and thus, abnormal activity such as that generated by early opioid exposure may alter normal

synaptic development producing changes in somatosensory processing and behavior that would

not occur in similarly exposed adults. Our group has demonstrated that neonatal rats may be more sensitive to low doses of morphine because there is selleck chemical extensive re-modeling of opioid receptor expression in the first 3 postnatal weeks (Rahman et al., 1998, Galeterone Rahman and Dickenson, 1999 and Beland and Fitzgerald, 2001). For example, at P14 spinal μ-opioid receptors (μORs) are limited to the dorsal horn, whereas they appear throughout the spinal grey matter at P7, and the density of binding is seen to decrease in the first 3 postnatal weeks, with peak binding at P7 that then falls to the adult level by P21. This abundance of μORs in early postnatal life could explain why exposure to morphine for 7 days, from P8 to P14, produces analgesia instead of tolerance (Rozisky et al., 2008). Thus, the greater expression of μORs at P7 in comparison to adult rats suggests a more widespread effect of morphine, acting both directly within the spinal cord and indirectly through larger termination profiles of primary afferents (Nandi et al., 2004). This, coupled with the over-expression of excitatory amino acid receptors, at the primary afferent-spinal cord synapse, supports a potential role for μORs in the normal maturation of nociceptive circuitry, and hence, disruption of this by exogenous administration of opioid agonists may have detrimental consequences for the maturation of pain circuitry (Thornton and Smith, 1998 and Thornton et al., 2000).