While the role of calcitonin gene-related peptide (CGRP) in headache and migraine is well established, Dr Isaac Chiu speaking at #AHSAM21 sought to unravel the role of CGRP in infection-induced pain. CGRP signalling to gut epithelium protects against Salmonella infection; conversely, blocking CGRP could enhance innate immunity and improve the outcome of skin infections.
CGRP activity in skin infections
Dr Isaac Chiu explained that nociceptor sensory neurons are specialized to detect microbial pathogens, protecting the body 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.1
Innate immune cells express CGRP receptors
CGRP is released from nociceptive terminals in skin and gut infections when activated by bacterial pathogens, which modulates RAMP1 on immune and epithelial cells.2 Acute targeting of CGRP may be useful in cases where CGRP inhibits innate immune activity (e.g., invasive skin infections) to benefit the outcome of infection.
Blocking CGRP could enhance innate immunity and improve the outcome of infection
Streptococcus pyogenes is a major cause of infections, including pharyngitis, impetigo, scarlet fever, boils, cellulitis, necrotising fasciitis, and the level of pain reported is often ‘out of proportion’ with early clinical manifestations. Flesh-eating bacteria hijack a pain response that suppresses host defense mechanisms.3
Targeting the peripheral nervous system and blocking neuro-immune communication may be a promising strategy to treat highly invasive bacterial infections. S. pyogenes produces pain during bacterial invasion through streptolysin S, which induces TRPV1 neurons to release CGRP into infected tissues.3 Botulinum neurotoxin A and CGRP antagonists block neuron-mediated suppression of host defense, thereby preventing and treating S. pyogenes necrotizing infection in animal studies.
CGRP protects against gut infections
In the gut, CGRP maintains gut epithelial homeostasis and the microbiome composition. Peyer’s patch M cells are entry points for enteric pathogens, and CGRP suppression of M cells protects against Salmonella infections.2
Extrinsic nociceptor neurons mediate protection from Salmonella infection by direct sensing and release of CGRP, which leads to suppression of M cell density and maintenance of segmented filamentous bacteria colonization of the ileum.2 On the other hand, long-term blockade of CGRP may lead to defects in gut epithelial barrier function and host defense against gut pathogens.
CGRP signalling to gut epithelium protects against Salmonella infection
Based on available animal data, Dr Chiu concluded that while blocking CGRP activity may offer a therapeutic approach to skin infections, people on anti-migraine treatments that target CGRP-RAMP1 signaling should be aware of the potential for chronic effects on the immune and gastrointestinal systems, that may include an increased susceptibility to infections.
AHSAM: American Headache Society Annual Meeting
CGRP: Calcitonin Gene Related Peptide
RAMP1: receptor activity-modifying protein 1
TRPV1: Transient Receptor Potential V1
BE-NOTPR-0068, approval date 08/2021
