Abstract
The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally acting muscarinic agonists, electrical stimulation of the vagus and treatment with nicotinic receptor agonists can all act systemically to reduce inflammation, although the responsible pathways are incompletely understood. While this ‘cholinergic anti-inflammatory pathway’ is widely viewed as a significant pathophysiological mechanism controlling inflammation, the evidence supporting this view is critically reviewed and considered inconclusive; an alternative pathway via sympathetic nerves is implicated. This review also discusses how cholinergic pathways, both neural and non-neural, may impact on inflammation and specifically arthritis. Nicotinic agonists have been reported to reduce the incidence and severity of murine arthritis, albeit an observation we could not confirm, and clinical studies in rheumatoid arthritis have been proposed and/or are underway. While the therapeutic potential of nicotinic agonists and vagal stimulation is clear, we suggest that the ‘cholinergic anti-inflammatory pathway’ should not be uncritically embraced as a significant factor in the pathogenesis of rheumatoid arthritis.
Highlights
Nervous and immune system interactions are likely to be occurring in arthritis, as exemplified by the observation that hemiplegic patients do not develop psoriatic arthritis on their denervated side [1]
For an action mediated presumptively by postganglionic parasympathetic nerves (Figure 1), the anti-inflammatory effects of vagal stimulation are not blocked by muscarinic antagonists such as atropine methyl nitrate [8], they are blocked by antagonists of β2 adrenoreceptors and are absent in mice lacking those receptors [16]
Janig and Green [58] have recently reviewed their studies on bradykinin-evoked plasma extravasation in the rat knee joint, which clearly showed that this inflammatory response depended in large measure on the presence of sympathetic nerve terminals in the joint but not on their neural activity or their preganglionic inputs
Summary
Nervous and immune system interactions are likely to be occurring in arthritis, as exemplified by the observation that hemiplegic patients do not develop psoriatic arthritis on their denervated side [1]. This last finding suggests that central cholinergic neurons (Figure 1) tonically release acetylcholine close to the muscarinic receptors that drive the anti-inflammatory action.
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