SUMMARYBoth neurogenic influences and the regulatory neuropeptide substance P (SP) have been implicated in the development of joint inflammation. Using the laser Doppler perfusion imaging technique to quantify relative changes in joint blood flow, the effects of nerve stimulation and topical SP application were examined in normal and chronically inflamed rat knee joints. Synovial inflammation was induced by unilateral intra-articular injection of Freund's complete adjuvant and experiments were carried out 1 week and 3 weeks later. Normal knees showed a frequency-dependent vasoconstriction in response to saphenous nerve stimulation over the range of 5-30 Hz and a dose-dependent vasodilatation in response to SP administration. These vasoactive responses were completely abolished in the chronically inflamed knee joint, the abolition persisting throughout the investigation. Since articular cartilage is critically dependent on synovial fluid formation for its nutrition, loss of neurovascular control of the synovial microcirculation could contribute to the degenerative changes that commonly accompany chronic inflammatory joint diseases.

SUMMARYAn imaging technique (laser Doppler perfusion imaging, LDI), based on measurement of backscattered Doppler-broadened laser radiation, was used to provide two-dimensional images of perfusion in the exposed rat knee joint capsule. In control animals, frequency-dependent constriction of knee joint blood vessels occurred during electrical stimulation of sympathetic nerve fibres whilst dose-dependent vasodilatation of these vessels was elicited by direct application of the sensory neuropeptide substance P (SP) to the capsule. Intra-articular injection of the neurotoxic agent capsaicin did not affect vasoconstrictor responses when tested 5-7 days later, but substantially reduced dilator responses to SP. These findings indicate that capsaicin is selectively neurotoxic for sensory unmyelinated fibres but not sympathetic postganglionic fibres and is also capable of modifying receptor-mediated effects of SP. LDI is a useful method for mapping tissue perfusion, particularly in structures such as joints where the spatial distribution of blood flow is heterogeneous.

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1 Experiments were performed to investigate the role of endogenously released tachykinins in the regulation of blood¯ow to the rat knee joint. Synovial perfusion was assessed by laser Doppler perfusion imaging, which permitted spatial measurement of relative changes in perfusion from control (pre drug administration), expressed as the percentage change. Most experiments were performed on the exposed medial aspect of the knee joint capsule. 2 Neither the selective tachykinin NK 1 receptor antagonist, FK888, nor the selective tachykinin NK 2 receptor antagonist, SR48968, signi®cantly in¯uenced synovial blood¯ow at doses of 10 712 , 10 710 and 10 78 mol. However, topical co-administration of these agents produced signi®cant dose-dependent reductions in basal synovial perfusion of 6.3+4.6, 12.0+3.4 and 19.9+2.6%, respectively; n=29. The non-selective tachykinin NK 1 /NK 2 receptor antagonist, FK224, also produced signi®cant (at 10 710 and 10 78 mol), but less potent, reductions in perfusion of 5.3+4.0, 8.4+2.2 and 5.9+2.8%, respectively; n=25. 3 Topical administration of the a 1 -, a 2 -adrenoceptor antagonist phenoxybenzamine elicited a 31.3+6.2% increase in blood¯ow which was substantially reduced to 10.4+3.8% by co-administration of the FK888 and SR48968 (both at 10 78 mol; n=8 ± 13), suggesting that normally there is sympathetic vasoconstrictor`tone' which is opposed by the vasodilator action of endogenous tachykinins. 4 One week after surgical interruption of the nerve supply to the knee joint, co-administration of FK888 and SR48968 (both at 10 78 mol) now produced slight vasodilatation (6.7+4.6%; n=9) which did not di er signi®cantly from vehicle treatment. Depletion of tachykinins from sensory nerve ®bres by systemic capsaicin administration also resulted in abolition of the vasoconstrictor e ect of FK888 and SR48968 (both at 10 78 mol), with these agents only producing a slight vasodilatation (2.5+5.3%; n=6). 5 By use of a near infra-red laser source it was possible to image knee joint perfusion transcutaneously, the overlying skin being left intact. In this more physiological situation, close intra-arterial injection of the combination of FK888 and SR48968 (both at 10 78 mol) again elicited vasoconstriction (48.8+16.2% reduction in blood¯ow; n=4). 6 These results indicate that endogenous tachykinins may be continuously released from sensory ®bres innervating the joint. Basal release of tachykinins could therefore be an important physiological in¯uence opposing sympathetic vasoconstrictor tone.

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