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The molecular basis of pain and its clinical implications in rheumatology


Nociceptive pain in response to peripheral noxious stimuli, and inflammatory pain resulting from tissue damage, serve as warnings that normal bodily function cannot resume until the stimulus abates or the tissue repairs. Stimuli cause numerous receptors, ion channels and other cellular machinery to respond, and propagate signals to the central nervous system, where this information is processed and perceived as pain. In healthy individuals, tissue damage results in physiologic—generally reparative—changes that lead to heightened sensory perception and, often, pain. In rheumatic diseases, the joint pain bears much in common with chronic inflammatory pain, but the underlying disease state is typically much more intricate and no reparative function is evident. Addressing the complex pains of rheumatic disease remains an ongoing challenge. Pain signaling pathways involve many molecular components that could potentially be targets for pharmacotherapeutic intervention, but the complexity of this system might also mean that multiple sites must be affected simultaneously to disrupt propagation of pain signals. In addition, to be therapeutically viable, pain drugs must be safe and not alter tactile sensory function, alertness or cognitive function. In this article we review the molecular functions in nociceptive, inflammatory and rheumatic pain pathways, and the therapeutic options they might offer.

Key Points

  • Nociceptive pain is a normal, physiological response to noxious stimuli that foretells the likelihood of tissue damage or indicates pathology

  • Numerous receptors, ion channels and signal transduction molecules convey sensory information (location, intensity and duration of the stimulus) from the periphery to the central nervous system, where the processing of these signals can result in the perception of pain

  • Despite dense innervation, healthy joints are not perceived as painful, but become subject to pain upon injury or pathology—particularly the pathology associated with rheumatic disease

  • The high numbers of known receptors and ion channels in pain suggest a wealth of novel targets for pharmacotherapy, and mechanism-based investigations are being made into manipulation of these targets

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Figure 1: The nociceptive pain pathway.
Figure 2: Functional states of nociceptor sodium channels in sensory conductance.
Figure 3: Depiction of some of the brain regions involved in ascending and descending pathways and pain signal processing.
Figure 4: The role of phosphorylation in TRPV1 signal transduction.


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Correspondence to Tarek A Samad.

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Bingham, B., Ajit, S., Blake, D. et al. The molecular basis of pain and its clinical implications in rheumatology. Nat Rev Rheumatol 5, 28–37 (2009).

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