One method for examining the location of opioid receptors is to use autoradiographic techniques. When this technique is used in rats in which the sciatic nerve is ligated, opioid receptors are found to accumulate proxi-mally and distally to the ligature in a time-dependent fashion suggesting that there is bidirectional axonal transport of these receptors. In another rodent model, non-inflamed paw tissue is known to contain some opioid receptors. When inflammation is induced by application of Freund's adjuvant to a paw, the density of opioid receptors increases in the paw massively. These opioid receptors are found in the cutaneous nerves and in immune cells infiltrating the surrounding tissue.
Using the same Freund's adjuvant model of inflammation, local injection of tumor necrosis factor or interleukin into the paw causes a dose-dependent increase in paw-pressure thresholds, or in other words a reduction in pain. This increase in paw-pressure thresholds is prevented by local injection of the opioid antagonist naloxone and by the mu-opioid-specific antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Tr-NH2). In animals pretreated with cyclosporin to suppress the immune system, the antinociceptive effect of the tumor necrosis factor is completely removed. It has been suggested, therefore, that cytokines release opioid peptides from immune cells of inflamed tissue, which act on opioid receptors present on sensory nerve terminals resulting in antinociception.
When DAMGO ([D-Ala(2),NMePhe(4), Gly(01)(S)],enkephalin), a mu-opioid ligand, is injected into tissue, the nociceptive effects of local irritant injection are reduced. In contrast, when DPDPE, a delta-opioid ligand is applied in a similar fashion, no change in nociception is observed. This suggests that peripheral mu-opioid receptors, and not delta-opioid receptors, are actively involved in nociceptive processing. Interestingly, in contrast to the central effect of opioids, there is a relative lack of antinociceptive tolerance to the effects of opioids on peripheral opioid receptors in inflamed tissue.
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