S.C. Cruwys

Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis

Abstract Rheumatoid arthritis (RA) is characterised by pain and tenderness not only over inflamed or damaged joints, but also over apparently normal tissues. Experimental models suggest that these features result from changes of sensitivity within both peripheral and central neurones, but direct evidence from human disease is lacking. At present, most clinical studies have evaluated overall pain experience rather than activity within components of the nociceptive pathway. Therefore, the aim of this study was to assess the use of a capsaicin‐based technique to quantify changes of neuronal sensitivity in patients with RA. First 20 &mgr;l of capsaicin in solution (0.03 mg/ml) was applied topically for 30 min to apparently normal skin on the forearm of control subjects and patients with RA. The subsequent development of mechanical hyperalgesia to pinprick stimuli was then measured at various time points using a 74.4‐mN von Frey hair. The relationship between the area of hyperalgesia and a number of clinical measures was determined. Capsaicin‐induced mechanical hyperalgesia was found to decline with age in normal subjects (r=0.47, P<0.01). The development of hyperalgesia had a similar time course in normal subjects and patients with RA. The maximum area of hyperalgesia, however, was substantially larger in 35 RA patients; 254.3±20.7 cm2, compared with 35 normal controls; 109±7.5 cm2 (P<0.001). An association was apparent between hyperalgesic area and a composite score of joint tenderness (r=0.47, P<0.01), but not with overall pain score or a systemic marker of inflammation. These results provide evidence for enhanced sensitisation of a population of sensory fibres in RA. Peripheral sensory activity over the forearms of rheumatoid patients has previously been shown to be normal and the results suggest the presence of enhanced central mechanisms in this disorder. The correlation between capsaicin‐induced hyperalgesia and joint tenderness in the RA patients implies that joint symptoms arise partially as a result of central, and not exclusively peripheral, factors. The study supports the use of capsaicin‐based techniques to explore nociceptive mechanisms in clinical disorders characterised by chronic pain.

Monoarthritis in the rat knee induces bilateral and time-dependent changes in substance P and calcitonin gene-related peptide immunoreactivity in the spinal cord.

Bilateral changes in the spinal cord and dorsal root ganglion content of the sensory peptides substance P and calcitonin gene-related peptide have been previously reported in animal models of arthritis which affect many joints within the body. The central nervous system has been implicated in the symmetry of joint involvement in human rheumatoid arthritis. We aimed to determine whether unilateral inflammation of the knee joint can also induce bilateral changes in the spinal cord. We have induced a monoarthritis in the knee joint of the rat and used quantitative immunocytochemistry to look at changes of these peptides in the dorsal horn of the spinal cord and the dorsal root ganglia. Furthermore we have examined the responses during the acute (three days) and the chronic (21 days) phases of the model. The data show that in the acute phase of the monoarthritis there is both an ipsilateral and contralateral response which increases the immunoreactive substance P and calcitonin gene-related peptide in the L4 level of the dorsal horn of the spinal cord. In the chronic phase of the monoarthritis, the contralateral side of the dorsal horn returned to control values whilst the ipsilateral side showed reduced amounts of immunoreactive substance P and calcitonin gene-related peptide compared to controls. We propose that the acute response, at three days, to unilateral inflammation is appropriate and has evolved to protect an organism against the original insult ipsilaterally, and the possibility of subsequent insult contralaterally.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of bradykinin B1 receptors in the maintenance of intra-articular plasma extravasation in chronic antigen-induced arthritis.

1 The role of bradykinin B1 and B2 receptors in bradykinin‐ and des‐Arg9‐bradykinin‐induced plasma extravasation in normal and inflamed rat knee joints was investigated by use of an antigen‐induced model of chronic arthritis. A modification of an Evans blue extraction technique allowed the unstimulated (basal) plasma extravasation to be assessed in this model. The contributions of bradykinin B1 and B2 receptors towards basal synovial plasma extravasation were determined. 2 In normal knees, intra‐articular injection of bradykinin (BK) induced plasma extravasation in a potent, dose‐dependent manner with a threshold of 0.01 nmol and an ED50 of 0.1 nmol. In day 5 arthritic knees, basal plasma extravasation was substantially enhanced. Lower doses of BK had no demonstrable effect and increases above basal extravasation were first observed at 0.1 nmol. Thereafter the dose‐response mirrored the response in normal knees and the maximal response was unaltered. 3 The B1 agonist, des‐Arg9‐BK, induced slight but significant plasma extravasation in normal knees but was less potent than bradykinin. This response was inhibited by the Bi receptor antagonist, des‐Arg9, [Leu8]‐BK. Lower doses of des‐Arg9‐BK bradykinin did not significantly increase basal extravasation in day 5 arthritic knees but, in contrast to BK, the maximal response was significantly enhanced. 4 The B2 antagonist, Hoe 140, inhibited BK‐induced plasma extravasation in normal joints over a dose‐range of 0.1‐1.0 nmol but was relatively inactive in day 5 inflamed knees. The B1 receptor antagonist, des‐Arg9, [Leu8]‐BK, was relatively inactive in normal joints but showed increased potency against BK‐induced plasma extravasation in day 5 arthritic joints. 5 Hoe 140 and des‐Arg9, [Leu8]‐BK both inhibited basal extravasation in arthritic joints on days 1 and 5 post‐challenge in a dose‐dependent fashion. Whilst Hoe 140 was the more potent inhibitor on day 1, it was less potent than des‐Arg9, [Leu8]‐BK on day 5. 6 Although the majority of responses to BK in normal tissue are mediated via B2 receptors, a small population of B1 receptors may exist in normal joint tissues. The data presented in this study suggest an evolving role for Bx receptors in the mediation of plasma extravasation in inflamed joint tissues. A role for BK antagonists in the treatment of arthritis is also suggested.

Sensory denervation with capsaicin attenuates inflammation and nociception in arthritic rats

The relatively few studies that have investigated the effects of the nervous system on chronic joint disease have reported conflicting results. We have reassessed the effects of capsaicin on experimental polyarthritis with particular reference to the relationship between changes in nociception and changes in process and outcome measures of disease activity. Capsaicin pretreatment significantly attenuated both joint swelling and disease outcome as determined by quantitative radiology and histology. There was a close correlation between process measures of inflammation and mechanical hyperalgesia in both the untreated and capsaicin treated arthritic groups. The results confirm a suppression of inflammation by capsaicin and imply that the nociceptive and pro-inflammatory (neurogenic inflammation) activities of capsaicin-sensitive fibres are closely linked such that stimuli which cause pain will also induce neurogenic inflammation and vice versa.

Increased capsaicin-induced secondary hyperalgesia as a marker of abnormal sensory activity in patients with fibromyalgia

In this study, capsaicin-induced secondary hyperalgesia was assessed as a marker of abnormal nociceptive processing in patients with fibromyalgia (FM). The area of mechanical secondary hyperalgesia induced by a standard solution of capsaicin placed on the volar forearm was measured in ten patients with FM and the results compared to those obtained in ten patients with rheumatoid arthritis (RA) and ten normal subjects. The area of secondary hyperalgesia was found to be substantially increased in both the FM and RA groups compared with controls. In the FM group the area of hyperalgesia correlated with the overall pain score and with the joint tenderness score. The results suggest that in FM there is enhanced sensitivity of nociceptive neurones at a spinal level, thereby supporting the concept of a generalised disturbance of pain modulation in this disorder.

The effects of calcitonin gene-related peptide on formation of intra-articular oedema by inflammatory mediators.

1 The temporal and quantitative effects of inflammatory mediators on plasma extravasation in the rat knee were investigated by use of a perfusion technique. 2 Intra‐articular perfusion of substance P (SP), bradykinin or histamine over a 5 min test period produced rapid‐onset and prolonged plasma extravasation in a dose‐dependent fashion. The rank order of potency was bradykinin > SP > histamine. 3 Calcitonin gene‐related peptide (CGRP) did not induce plasma extravasation but enhanced substance P‐induced plasma extravasation in a dose‐dependent fashion. A 5 min co‐perfusion of the two agents produced short‐term enhancement lasting 10 min while continuous co‐perfusion produced enhancement for the duration of the perfusion. 4 A 5 min perfusion of CGRP enhanced plasma extravasation when co‐perfused with bradykinin but not histamine. However, when CGRP and histamine were continuously co‐perfused over a 20 min test period, an enhanced response was apparent. 5 The results indicate that intra‐articular perfusion of CGRP enhances synovial plasma extravasation induced by agents that increase vascular permeability, but suggest that the response is not uniform and is critically dependent on the duration of perfusion within the joint.

Role of substance P in inflammatory arthritis

The neuropeptide substance P (SP) has wide ranging effects on many cell types. Nilsson et al showed that SP could stimulate connective tissue cell growth by stimulating DNA synthesis in human skin fibroblasts and arterial smooth muscle cells in vitro. 1 Substance P has also been implicated in inflammation owing to its effects on cells associated with acute and chronic inflammatory responses. Substance P promotes chemotaxis of human monocytes, and this appears to be an SP receptor mediated effect as it is blocked by D-amino acid analogues of sp.2 Substance P mediates macrophage activation, including enhancement of the oxidative burst with production of significant amounts of the superoxide anion, hydrogen peroxide, and release of prostaglandin E2, thromboxane B2, and leukotriene C4.3 4 A later event induced by SP is the release of lysosomal enzymes from activated macrophages.4 Direct injection of SP into human skin produces a wheal and flare reaction as seen with histamine, but SP is about 100 times more potent.5 Substance P induces the specific release of histamine from mast cells,6 which will produce vasodilatation, oedema, and an increase in vascular permeability-that is, SP can produce an inflammatory response by a direct or an indirect effect. It is apparent that SP may have a role in inflammation and perhaps is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. This review attempts to tie together past and current ideas about SP and inflammatory arthritis.

Effect of three animal models of inflammation on nerve fibres in the synovium.

OBJECTIVES--Both sensory and sympathetic nerve fibres are depleted in the synovium in rheumatoid arthritis (RA). The hypothesis that the induction of an inflammatory response in the synovium is capable of causing depletion of nerve fibres was tested. METHODS--To investigate this phenomenon experimental arthritis in the rat was induced by three different methods and the synovium was examined for evidence of nerve depletion by immunocytochemistry. RESULTS--In a synovitis induced by latex spheres, a mainly macrophage foreign body type reaction, no nerve depletion was seen. In contrast both in an antigen-induced and a hydrogen peroxide-induced model of arthritis nerve fibre depletion was observed. This appeared to affect sensory and sympathetic nerve fibres equally. Nerve fibre depletion was only seen in areas of inflammatory cell infiltration indicating that a mixed lymphocyte and macrophage population of cells may be necessary for this effect. CONCLUSIONS--An inflammatory response, containing lymphocytes and macrophages, in the synovium is capable of the depletion of the finely myelinated and unmyelinated neuropeptide-containing nerves.

Role of the sympathetic nervous system in chronic joint pain and inflammation.

A substantial body of evidence gathered from a variety of diseases points to a critical interaction between the sympathetic nervous system and the inflammatory cascade. An important sympathetic component to rheumatic disease is indicated by the observation that symptoms in both reflex sympathetic dystrophy and rheumatoid arthritis may be alleviated after regional sympathectomy. 1 Clearly, attempts to explain pathophysiological mechanisms must take observations such as these into account. This review summarises the evidence for a sympathetic influence on rheumatic disease and speculates on the mechanism by which this may arise.

The neurogenic contribution to synovial leucocyte infiltration and other outcome measures in a guinea pig model of arthritis.

A neurogenic contribution to joint inflammation has been demonstrated in rat adjuvant arthritis, however as inflammatory mechanisms vary between species it is unclear whether these observations can be applied more generally. The aim of this study was to assess the neurogenic contribution to cellular infiltration and other outcome measures in a guinea pig model of arthritis. Compared to arthritic controls, animals pre-treated with capsaicin at doses sufficient to reduce sensory activity exhibited a significant attenuation of both mechanical and thermal hyperalgesia. Measures of inflammation, including swelling and radiological scores were also improved. Furthermore, capsaicin selectively reduced synovial T cell infiltration whereas no difference was seen with respect to synovial macrophages. These observations confirm a neurogenic component in guinea pig arthritis and indicate a selective sensory influence on T cell activity within the chronically inflamed joint. As T cells are strongly implicated in the pathogenesis of rheumatic disease, such an influence may serve to explain some of the clinical features observed in these disorders.