substance-p-(4-11)--pro(4)-trp(7-9-10)- and Synovitis

Substance P (SP) injected into the synovial cavity of the rat knee resulted in an inflammatory response as measured by plasma protein extravasation into the joint capsule. This response was dose dependent over the range of approximately 4 microM to approximately 200 microM. Part of this inflammatory response was mediated via mast cells as pre-treatment of the animals with a mast cell degranulator (compound 48/80) resulted in a 66% reduction of the response. A direct effect of SP on the vascular receptors may also contribute to the inflammatory response as pre-treatment with the substance P antagonist (SPA) D-Pro4 D-Trp7,9,10 SP4-11 also reduces the inflammatory response. Intra-articular injections of the H1 blocker diphenhydramine or the H2 blocker cimetidine significantly blocked the SP-induced inflammatory response. The 5-hydroxytryptamine (5-HT) antagonist methysergide proved to be even more potent in blocking the SP-induced inflammatory response. No synergistic inhibition was observed with combinations of the different antagonists. Intra-articular injections of 5-HT elicited a much more pronounced inflammatory response than that produced by a 10-fold higher concentration of histamine. The results suggest that SP produces increased vascular permeability partly via direct actions on the blood vessels and partly via mast cells. The inflammatory response occurring via mast cells appears to be mediated by histamine and to a greater extent by 5-HT.

Topics: Animals; Cimetidine; Diphenhydramine; Histamine; Knee Joint; Male; Mast Cells; Methysergide; Peptide Fragments; Rats; Rats, Inbred Strains; Substance P; Synovitis

The pathophysiology of acute joint inflammation remains unclear. Evidence is available to suggest a neurally mediated component to the inflammatory process. Acute joint inflammation in the rat knee, induced by intra-articular injection of 2% carrageenan, was reduced by 44% in animals whose knee had previously been injected with 1% capsaicin, while chronic joint denervation produced a 37% reduction. These results indicate a significant neurogenic component in this model of acute joint inflammation. Substance P may be the mediator of this response as intra-articular injection of this agent provoked an acute inflammatory response. Pretreatment of the test knee with the substance P antagonist d-Pro4,d-Trp7 9 10-SP(4-11), however, resulted in a 93% reduction of the inflammatory response to carrageenan. This unexpectedly large effect suggests that this substance P antagonist blocks both neurogenic and non-neurogenic mediators of inflammation. Sympathetic efferent fibres innervating the knee joint were not found to contribute to the neurogenic component of the inflammatory process.

Topics: Animals; Capsaicin; Carrageenan; Hindlimb; Inflammation; Joints; Peptide Fragments; Rats; Rats, Inbred Strains; Substance P; Synovitis