Inflammation without pain: Immune‐derived opioids hold the key

Abstract

Visceral pain is commonly associated with acute or remitting inflammatory bowel disease (IBD). In marked contrast, chronic IBD is often painless, even in the presence of active inflammation. This suggests that inflammation in itself is insufficient to sustain altered nociceptive signaling and raises the possibility that there is an endogenous analgesic system in effect in chronic disease. A new study by Basso et al. published in this issue of Neurogastroenterology & Motility provides additional support for an immune‐mediated mechanism that suppresses visceral hypersensitivity. The authors examined visceral pain in the IL‐10‐piroxicam model of chronic colitis, which differs from other experimental IBD models in that it involves immune suppression. During active inflammation, responses by these mice to graded increases in colorectal distension were equivalent to healthy controls, consistent with normal afferent signaling. However, treatment with a peripherally restricted opioid receptor antagonist resulted in marked visceral hypersensitivity to the same stimuli. This effect was attributed to the production of endogenous opioids by colitogenic CD4+ T cells present in the mucosa. This mini‐review provides a brief overview of analgesia by immune‐derived opioids under inflammatory conditions and highlights how the work of Basso et al. contributes to this area of research. Potential pharmacological approaches to harness or mimic this system are provided. These strategies may prove to be an effective means through which targeted and sustained relief of IBD pain may be achieved.

Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis

“…To limit opioid use disorders, a variety of strategies have been proposed including biased ligands [28,38] or ligands specific for receptor splice-variant [27]. Because these approaches only partially overcome centrally mediated side effects such as addiction, alternative strategies based on the endogenous mechanisms of pain regulation in periphery are under investigation [8,14,26,41]. They consist in locally sustaining the endogenous opioid activity [13,35] or in activating peripheral opioid receptors [15,25] that may be targeted only in an acidic inflammatory environment [2,20,23,37,40].…”

Pain Management in a Model of Interstitial Cystitis/Bladder Pain Syndrome by a Vaccinal Strategy

“…We have previously demonstrated that this property requires their activation by antigens (12,17). Because peripheral delivery of opioids is preferred to achieve analgesia, mainly because it avoids central side effects (18)(19)(20)(21)(22), we hypothesize that, as previously shown in intestinal inflammatory disorders (23), recruitment of opioid-producing T cells may represent an interesting strategy to alleviate pain in IC/BPS (24,25). Therefore, a vaccine strategy that triggers both T cell recruitment and local opioid release appears as a promising therapeutic option in the pain management in IC/BPS.…”

Peripheral Opioid Receptor Blockade Enhances Epithelial Damage in Piroxicam-Accelerated Colitis in IL-10-Deficient Mice

“…Of note, even in the IL-10-deficient mouse model mimicking severe infantile Crohn’s disease associated with IL-10 loss of function, colitogenic CD4 + T lymphocytes conserve their analgesic activity [ 13 ]. Altogether these observations strengthen the rationale of a number of potential therapeutic strategies which propose to enhance or mimic immune-mediated endogenous opioid activity in chronic intestinal inflammatory diseases [ 14 , 15 , 16 ]. These therapeutic approaches aim at targeting opioid receptors in the periphery [ 17 , 18 , 19 ] and, for some of them, opioid receptors specifically located within the inflamed tissue [ 1 , 20 , 21 , 22 , 23 , 24 ] or at reinforcing endogenous immune-derived opioid tone [ 25 , 26 ].…”