Summary Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviors. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils/monocytes is not necessary for Staphylococcus aureus induced pain in mice. Mechanical and thermal hyperalgesia parallels live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin alpha-hemolysin through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions.

After nerve injury maladaptive changes can occur in injured sensory neurons and along the entire nociceptive pathway within the CNS, which may lead to spontaneous pain or pain hypersensitivity. The resulting neuropathic pain syndromes present as a complex combination of negative and positive symptoms, which vary enormously from individual to individual. This variation depends on a diversity of underlying pathophysiological changes resulting from the convergence of etiological, genotypic and environmental factors. The pain phenotype can serve therefore, as a window on underlying pathophysiological neural mechanisms, and as a guide for developing personalized pain medicine.

The peripheral nervous and immune systems are traditionally thought of as serving separate functions. This line is, however, becoming increasingly blurred by new insights into neurogenic inflammation. Nociceptor neurons possess many of the same molecular recognition pathways for danger as immune cells and in response to danger, the peripheral nervous system directly communicates with the immune system, forming an integrated protective mechanism. The dense innervation network of sensory and autonomic fibers in peripheral tissues and high speed of neural transduction allows for rapid local and systemic neurogenic modulation of immunity. Peripheral neurons also appear to play a significant role in immune dysfunction in autoimmune and allergic diseases. Therefore, understanding the coordinated interaction of peripheral neurons with immune cells may advance therapeutic approaches to increase host defense and suppress immunopathology.