We have previously shown that the kappa-opioid agonist, asimadoline, produces time-dependent changes in neuropeptide concentrations in the joints of rats with chronic arthritis. We hypothesized that asimadoline acts on peripheral terminals to modulate substance P (SP) release. To address this hypothesis, here we have examined neuropeptide expression in their source cells in dorsal root ganglia (DRG) that innervate the joint, as well as in non-neuronal tissue, after treatment with asimadoline. We found an increased production 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 calcitonin gene-related peptide-alpha (alpha-CGRP) in DRG cells but had no effect on the very low expression of neuropeptides in non-neuronal tissue. The fact that SP synthesis is attenuated by asimadoline accords with our hypothesis that the increased tissue levels of SP result from kappa-mediated pre-synaptic inhibition of release leading to augmented tissue stores. These in vivo data confirm literature findings that opioids inhibit SP release from peripheral endings of primary afferent fibres.