The Role of Interleukins and Nitric Oxide in the Mediation of Inflammatory Pain and its Control by Peripheral Analgesics

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Abstract
Tissue injury or the presence of foreign material initiates a series of pathophysiological events that may manifest as inflammatory pain. The physicochemical characteristics of the initiating factor trigger the release of a unique range of pain mediators that control the threshold and activation of nociceptors. It has been suggested that many nociceptors associated with inflammatory pain are dormant, and are activated by cyclo-oxygenase metabolites and sympathomimetic amines into a state of hyperalgesia. In this state, pain receptors may be activated by previously ineffective stimuli. The relative contribution of the mediators to the activation process varies with the experimental model or the pathophysiological process involved. The mechanisms that control the activity of the pain receptor are unfolding. Indeed, research has shown a central role for bradykinin (released from plasma) and cytokines (released from tissues and resident cells) in this process. The release of tumour necrosis factor-α (TNF-α) initiates the release of interleukin-1 and interleukin-8, which in turn liberate cyclo-oxygenase metabolites and sympathomimetic amines, respectively. In some models of inflammatory pain, bradykinin causes hyperalgesia via release of TNF-α. Drugs blocking cyclo-oxygenase (aspirin-like drugs), or those antagonising the effects of sympathomimetic amines (β-blockers), prevent sensitisation of the pain receptors. However, during hyperalgesia only specific types of analgesics are capable of nociceptor downregulation. It is assumed that sensitisation of nociceptors is due to increased concentrations of cAMP/Ca++ in the sensory neurons. The effect of increased cAMP concentrations may be counteracted by stimulation of the arginine/nitric oxide/cGMP pathway. Peripherally acting opiates and dipyrone are examples of analgesics that act via this mechanism. The analgesic effects of glucocorticoids and nimesulide appear to be attributable to inhibition of cytokine release.