Effects of the peripherally selective kappa-opioid asimadoline, on substance P and CGRP mRNA expression in chronic arthritis of the rat

We have previously shown that the kappa -opioid agonist, asimadoline, produ ces time-dependent changes in neuropeptide concentrations in the joints of rats with chronic arthritis. We hypothesized that asimadoline acts on perip heral terminals to modulate substance P (SP) release. To address this hypot hesis, here we have examined neuropeptide expression in their source cells in dorsal root ganglia (DRG) that innervate the joint, as well as in nonneu ronal tissue, after treatment with asimadoline. We found an increased produ ction of SP and CGRP in untreated chronic arthritic animals which supports our previous finding of increased SP content in the joint. More importantly , the kappa -opioid asimadoline reduced the expression of both SP and calci tonin gene-related peptide-alpha (alpha -CGRP) in DRG cells but had no effe ct on the very low expression of neuropeptides in non-neuronal tissue. The fact that SP synthesis is attenuated by asimadoline accords with our hypoth esis that the increased tissue levels of SP result from Ic-mediated presyna ptic inhibition of release leading to augmented tissue stores. These in viv o data confirm literature findings that opioids inhibit SP release from per ipheral endings of primary afferent fibres. (C) 2000 Harcourt Publishers Lt d.