Table A1.
Summary of disease-specific MC-mediated nociceptive mechanisms.
| Pain Model | Proposed Role of Mast Cells | Inhibitors | References |
|---|---|---|---|
| Mast cell disease | MC being the major player in mast cell disease it is hard to pinpoint a single mechanism or pathway for pain in MCAD. | MC stabilizers, antihistamines, leukotriene inhibitors along with conventional opioids. | HS [39,40,41] |
| Migraine | Mediators released from dural MCs can sensitize meningeal nociceptors. Histamine can enhance nociception via histamine receptors on meningeal nociceptors. MC-mediated SP and CGRP released from trigeminal nerves can also contribute to further MC activation and continuous sensitization. Serotonin has an anti-nociceptive effect and can block MC activation at the meningeal level. MC mediators sensitize neuronal cells via acid-sensing ion channels ASIC3 (not TRPV1) in MC-induced low pH conditions at the dural level. | H1R antagonist mepyramine; Serotonin-1 receptor agonists dihydroergotamine and sumatriptan; ASIC3 blocker APETx2. | HS [47,48,49,50,51,52,53,63] RM [35,57,58,59,60,61,62,64,65,66,70] FM [63] |
| Pelvic pain IC/BPS | SP released from bladder nerve fibers activates MCs via NK1R. In turn MC-derived histamine can further sensitize the primary afferent fibers via histamine receptors, and subsequently may contribute to increased central nociception via CaMKII induction. NGF may also play an important role in MC-mediated IC/BPS. | H1R antagonists—diphenhydramine, hydroxyzine, cetirizine (10 mg/kg); H2R antagonists—cimetidine, ranitidine, famotidine; NK1R antagonists—gabapentin and L-703,606; CaMKII inhibitor KN-93. | HS [74,75,76,77,78,79,80,81,82,83,84,85,86] RM [87,88,89,90,91,95,96,97,98,99,100,250] |
| CP/CPPS | Increased MC counts and associated degranulation may induce tryptase-PAR2 activation of sensory DRG neurons while histamine may promote peripheral sensitization. CCL2 and CCL3 can also contribute to MC correlated central sensitization. NGF released from nerve endings by MC activation may contribute to further MC recruitment. | Cromolyn; H1R antagonist cetirizine; H2R antagonist ranitidine; NGF neutralizing antibody AB-256-NA. | HS [102,103,104,106,107] RM [102,105,107,108] |
| CPPW | DAMPs from menstruation can activate MCs via TLRs, and MC degranulation products can lead to TRPV1-mediated nociceptive sensitization. Sensitized neurons can release SP and CGRP leading to increased MC activation. Also, sustained activation of MCs by estrogen can be a result of enhanced biosynthesis of estrogen via prostaglandin released from MC. | Anti-CCL2/JE (AB479NA) and anti-CCL3 (AB450NA) Leukotriene antagonist zafirlukast. | HS [31,111,112,113,114,115,116,117] RM [124,125] |
| Irritable Bowel Syndrome | Direct nerve fiber and mast cell structural interaction may induce pain. Histamine may be involved in IBS pain as well. Tryptase-PAR2 axis via TRPV1 and Ca2+ mobilization can contribute to sensitization of enteric nerves. Tryptase can contribute epithelial barrier dysfunction as well. MC mediator NGF can promote visceral hyperalgesia via modulation of DRG neuron plasticity and also via mucosal dysfunction to promote MC-nerve fiber interaction. Pathologic MC activation is seen in most therapy-resistant IBS patients. | MC stabilizer cromolyn; MC stabilizer with H1R antagonist property ketotifen. | HS [32,43,134,135,136,137,138,140,141,142,145,147,148,152,153,154,160,251] RM [144,152,153,157,158,159] |
| Vulvodynia | Increased MC infiltration, MC degranulation and hyper-innervation in vulvar region are associated with peripheral nociceptive sensitization and hyperalgesia. Allergic MC activation may also be a contributing factor. | ----------------- | HS [163,164,165] RM [166] |
| Complex regional pain syndrome | SP signaling mediates MC activation and correlated hypersensitivity via NK1 receptors. Increased and activated MCs may also activate keratinocytes and lead to PAR2-TRPA1 mediated nociception. | NK1R antagonist LY303870 | HS [173] RM [145,174,175,176,177,179,180,181,182,183] |
| Venom-induced hyperalgesia | MC degranulation may excite the voltage gated sodium channels of the peripheral and central neuronal cells. MC derived histamine sensitizes the nerve fibers. | MC stabilizer cromolyn; H1R antagonists chlorpheniramine, pyrilamine; H2R antagonist cimetidine.. | RM [184,185,186,187] |
| Fibromyalgia | Hypothalamic-pituitary-adrenal axis (HPA) may be involved in MC-mediated nociception. CRH released from HPA and also SP released from nerve fibers can activate MCs initiating a neuroendocrine cycle of feed-forward nociceptive sensitization. | MC stabilizer with histamine antagonistic property ketotifen. | HS [203,204,207] |
| Self-injurious behavior associated pain | Stress and abnormal innervation induced SP release may contribute to sustained activation of nearby MCs. MC mediators can further sensitize primary afferent fibers contributing to sustained pain. | MC stabilizer cromolyn. | HS [217,218,219,220] |
| Cancer pain | MC activation by morphine may lead to increased release of SP from nerve endings via tryptase-PAR2 axis, and SP can further contribute to sustained neurogenic inflammation and pain in cancer. | ------------------ | HS [226,227,228,229,230] RM [231] |
| Sickle cell pain | MC-derived tryptase (via PAR2-TRPV1) contributes to SP and CGRP release from peripheral nerve fibers. SP can further activate MC and MC mediators can further sensitize peripheral and central nervous system leading to sustained pain and hyperalgesia. MC activation by opioids such as morphine imparts resistance to therapy. | MC stabilizer Cromolyn; MC inhibitor Imatinib; Nociceptin agonist AT-200. | HS [234,235,236] RM [34,238] |
| Post-operative hyperalgesia | MC-derived tryptase may contribute to pain via PAR2. | MC stabilizer cromolyn and ketotifen; PAR2 antagonist ENMD-1068. | RM [122,239,241] |
| Neuropathic pain | Tryptase-PAR2-TRPV1/TRPV4/TRPA1 pathway contributes to MC-mediated pain. | PAR2 antagonist FSLLRY-amide. | RM [36,242] |