What is the cause of the pain produced during an infection? Until now it was thought that it is originated by the inflammatory response triggered by immune-derived substances such as cytokines, prostaglandins and growth factors. However, in a recent study published in Nature, researchers from Harvard University found that some peptides in bacteria can directly activate nociceptors therefore producing pain, without requiring the activation of the immune system. Furthermore, they found that neuropeptides released by nociceptors produce a direct immunomodulatory response.
In a first set of experiments the authors caused an infection on the hindpaws of mice (by local inoculation of the bacteria S.aureus) and then assessed the mechanically and thermally-induced pain. They found that the pain intensity is directly correlated to the bacterial load, but not with swelling or the quantity of immune cells and cytokines present in the site of infection. Using genetically-modified mice, this group also found that the pain caused by the bacterial load was not produced through the activation of the immune system by S. aureus.
In order to elucidate which bacterial elements were causing pain, the activity of nociceptive cells of the dorsal root ganglion (DRG) was measured using an electrophysiology technique (patch-clamp) and calcium imaging. The research team found that two bacterial products (N-formylated peptides and pore-forming toxin) produce higher levels of electrical activity and an increase in calcium influx in DRG nociceptive neurons.
Finally this group studied the role of nociceptors in modulating the immune response. They used genetically-modified mice that have a total lack of nociceptors. After S.aureus infection these mice displayed increased tissue swelling and a greater local infiltration of neutrophils relative to control littermates; which suggests that the nociceptor ablation leads to an increased local inflammatory response.
In summary this research team postulates that the direct activation of nociceptors by bacterial products could be the principal mechanism leading to pain; such finding is relevant since could improve the current treatments for painful infections. Moreover, the discovery of the down regulation in the local inflammatory response mediated by nociceptor activation is remarkable since this mechanism could be used by some pain-producing bacteria to increase their virulence.
Bacteria activate sensory neurons that modulate pain and inflammation.
Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, Waigner B, Strominger A, Muralidharan S, Horswill AR, Bubeck Wardenburg J, Hwang SW, Carroll MC, Woolf CJ.
Nature. 2013 Sep 5; 501(7465):52-7. doi:10.1038/nature12479. Epub 2013 Aug 21.