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

Abstract

Current analgesic treatments for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) are limited. Here, we propose a novel antinociceptive strategy exploiting the opioid-mediated analgesic properties of T lymphocytes to relieve from bladder pain. In a chronic model of IC/BPS in rats, we show that a secondary T cell response against intravesically administered ovalbumin prevents from visceral pain in OVA-primed animals. The analgesic effect is associated with the recruitment of T lymphocytes within the inflamed mucosa and is reversed by naloxone-methiodide, a peripheral opioid receptor antagonist. Similarly, intravesical instillation of BCG or tetanus toxoid antigens in vaccinated rats protects from pain in the same model. We show opioid-dependent analgesic properties of local vaccine antigen recall in a preclinical rat model of chronic cystitis. Since BCG bladder instillation is regularly used in humans (as anticancer therapy), our results open it as a new therapeutic positioning for a pain management indication for IC/BPS patients.

Inflammation-Independent Antinociceptive Effects of DF2755A, a CXCR1/2 Selective Inhibitor: A New Potential Therapeutic Treatment for Peripheral Neuropathy Associated to Non-Ulcerative Interstitial Cystitis/Bladder Pain Syndrome

“…In line with previous studies ( Augé et al, 2020 ; 2021 ), repeated injections of CYP-induced peripheral neuropathy in female SD rats, dramatically decreasing the withdrawal thresholds to noxious stimuli measured 24 h after the last CYP administration at the level of low abdomen ( Figure 1A ) and hind paws ( Figure 1B ). The histological analysis showed that no inflammatory infiltrate and no urothelial hyperplasia were detectable in rat urinary bladders after chronic CYP administration ( Figures 2A,C ), thus resembling human non-ulcerative IC ( Augé et al, 2020 ).…”

“…In the acute model, single CYP intraperitoneal injection (150–200 mg/kg) induces massive urinary bladder inflammation, visceral pain, and tissue hemorrhage, which are characteristics of the ulcerative form of human IC ( Augé et al, 2013 ); otherwise, rats receiving multiple injections of lower doses of CYP show little or no inflammatory cell infiltration in the bladder, resembling the features of chronic non-ulcerative human IC/BPS ( Augé et al, 2020 ). In this latter chronic model, repeated CYP administration (25–100 mg/kg each dose) induces peripheral neuropathy in rats, which is characterized by abdominal pain associated with increased mechanical sensitivity in the hind paws and abdominal area, indicative of a central sensitization ( Augé et al, 2020 ; 2021 ) and similar to the neuropathic pain behavior observed in IC/BPS patients ( Fariello and Moldwin, 2015 ).…”

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

“…Macroscopic damage was evaluated using a scale ranging from 0 to 11: erythema (absent (0), length of the area less than 1 cm (1), more than 1 cm (2)), edema (absent (0), mild (1), severe (2)), strictures (absent (0), one (1), two (2), more than two (3)), ulceration (absent (0), present (1)), mucus (present (0), absent (1)), and adhesion (absent (0), moderate (1), severe (2)). Bowel wall thickness was measured with an electronic calliper at 0.5 cm above the anus (colorectum).…”

“…In this context, the finding that endogenous opioids locally produced by mucosal CD4 + T lymphocytes [4,[9][10][11][44][45][46] alleviate inflammation-induced visceral pain represents an opportunity to improve opioid therapy. Beyond the potential therapeutic use of effector memory T lymphocytes including active vaccination [1,5] or passive T cell transfer (immunotherapy) [24,49], a better knowledge of the opioid receptor(s) involved in the peripheral analgesic effects of T lymphocytes might also refine prescription of opioid medications.…”

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

“…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 ]. Considering that opioid drugs also display anti-inflammatory effects [ 27 , 28 , 29 , 30 ], it may be expected that the alternative therapeutic strategies promoting mucosal endogenous opioid tone may also improve clinical outcomes in inflammatory bowel diseases (IBD).…”