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Do microbes gain when there is no pain

Abstract for 2022 ISEMPH annual meeting in Lisbon, Portugal:

Pain is among the most common reasons a patient seeks medical care. However, pain itself is not always problematic. Responding to painful stimuli protects an organism from physical harm. Here we suggest another function: pain protects organisms from pathogens. Protection from infection is orchestrated by local effects of pain neuron activation, regulation of pain at the CNS, and subjective experience of pain. Mechanisms underlying the regulation of pain and immunity overlap considerably, suggesting that pain may be another arm of the immune system. Notably, pain is used by clinicians as a sign of likely infection in wounds and after surgery. Some pain neurons express receptors that detect pathogens; when activated, these neurons initiate immune responses against pathogens. One prediction of this hypothesis is that pathogens should engage strategies to block pain. Accordingly, SARS-CoV2 recently was shown encode peptides that interfere with pain. Other parasites and bacteria also disrupt pain signaling, including M. leprae which destroys pain neurons. Because some pathogens block pain, it could be adaptive for hosts to have an anticipatory counter-response against microbial manipulation of the pain system. This could lead to higher pain sensitization. We discuss treatment implications for chronic pain, long COVID, and opioid dependence. 

Authors: Kevin Lozo, Athena Aktipis, Joe Alcock

References of special merit:

Oaten et. al 2015 The Effect of Disgust on Pain Sensitivity

Chiu. 2018 Infection, Pain and Itch

 Cohen et al (2019). Cutaneous TRPV1+ Neurons Trigger Protective Innate Type 17 Anticipatory Immunity

Table. Effect of opioid analgesics on infection
Abdominopelvic surgeryPreoperative opioid useIncreased postoperative healthcare utilization and morbidity[81]
Hospitalized patients receiving broad spectrum antibioticsModerate to high opioid useIncreased risk of Clostridiales difficile infection[82]
Patients with and without HIVPrescription opioid use 12 months priorIncreased risk of community acquired pneumonia[83]
Invasive pneumococcal diseaseCurrent opioid useIncreased risk of invasive pneumococcal disease[84]
Rheumatoid arthritisCurrent opioid useIncreased risk of hospitalization for infection[85]
CirrhosisChronic opioid useIncreased risk of endotoxemia, dysbiosis, and readmission[42]
HIVOpioid abuseAccelerated HIV progression[86]
Crohn’s diseaseNarcotic analgesic treatmentIncreased risk of serious infection and mortality[47]
Table 1. Opioids increase the risk of infection, as do NSAID analgesics
Pain-Blocking MechanismPathogen
Interference with TRPV1 nociceptorsPorphyromonas gingivalis and SARS-CoV2
Destruction of sensory neurons and anesthesiaMycoplasma leprae and Mycobacterium ulcerans
Production of opioid and opioid-like compound productionToxoplasma canis, Ascaris suum, Dracunculus medinensis, Schistosoma mansoni, Plasmodium berghei
Interference with opioid receptor signalingEscherichia coli
Synthesis of proteins that mimic enzymes responsible for morphine synthesis in the opium poppyPseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii
Table 2. Multiple pathogens inhibit pain signaling
TRPV1 neurons detect pathogen molecules (red spiky ball) and trigger leukocyte recruitment in tissues distant from the original infection. This process is called “innate anticipatory immunity.”

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