Mast cells are emerging players in physiological and pathological pain pathways. Mast cells are frequently found in close proximity to nociceptive neurons and therefore can participate in juxtacrine signaling in neuro-immune synapses (1). Mast cells induce nociceptor activation through the release of chemical mediators during degranulation and can be activated by mediators released from nociceptors upon injury (2).
In a model of passive cutaneous anaphylaxis (PCA) in the rat hind paw Lavich and colleagues (3) demonstrated transient increased thermal hyperalgesia following plantar anti-DNP-IgE sensitization and DNP challenge regulated by the synergistic interaction of histamine, bradykinin, and 5-hydroxytryptamine – all likely products of mast cell degranulation (3). Piovezan and colleagues observed abrogation of OVA-induced hyperalgesia by chemical depletion of mast cells in the hind paws of sensitized mice (4), demonstrating that active sensitization and challenge leads to pain that is dependent on mast cell degranulation. The injection of IL-6, TNFα, IL-1β, and IL-8, cytokines readily secreted by mast cells, can independently evoke hyperalgesia (5). Chatterjea and colleagues showed that genetically mast cell-deficient C57BL/6-KitW-sh/W-sh mice have significantly reduced thermal and mechanical plantar hyperalgesia after intra-plantar injection with mast cell secretagogue compound 48/80 (c48/80) compared to wild-type mice; these responses are restored following reconstitution of the hind paw with bone marrow cultured mast cells (6). These findings supported an earlier observation that injection of c48/80 into the forearms of young male volunteers caused changes in pain sensitivity in the skin surrounding the sites of administration (7).
Mast cells in pre-clinical models of inflammatory and chronic pain disorder:
Mast cells have been shown to be important in rodent models of migraine (16, 17) with systemic mast cell degranulation causing nociceptor activation in the dura as well as in the spinal cord. Mast cells contribute to mechanical cystitis pain via histamine receptor 1 and 2 signaling in a murine model of pseudorabies virus (PRV)-induced pelvic pain (18). NK-1 and histamine receptor 2 antagonists have been shown to mitigate bladder-associated pelvic pain, suggesting that blockade of mast cell-mediated regulatory mechanisms may have therapeutic potential in the treatment of cystitis-related pain (19). Bonavita and colleagues demonstrated that mast cell stabilizer sodium cromoglycate (SCG) inhibited Bothrops jararaca venom-induced release of histamine and leukotriene C4 in vitro and abrogated venom-induced hyperalgesia in vivo in rats (20). Mast cell are also critical for pain sensation in rodent models of post-operative pain (21) and neuropathic thermal and mechanical hyperalgesia caused by the ligation of the sciatic nerve in rats (22).
Mast cell-neuron interactions in pain pathways:
Mast cells residing in close proximity to unmyelinated nerve fibers, such as the nociceptive C-fibers, can undergo ultrastructural alterations that allow differential or selective “piecemeal degranulation” (3). This is particularly important for understanding pain conditions where mast cell-nerve associations have been documented, such as inflammatory bowel syndrome (16) and vulvodynia (12, 14). Adhesion molecules such as N-cadherin and cell adhesion molecule-1 (CADM-1) facilitate mast cell-nerve junctions (23). Mast cell mediators NGF and TNF-a influence neuronal growth, while mast cell-derived NGF has also been shown to lower the threshold of nociceptor firing through its binding to TRK1-transforming tyrosine kinase protein (trkA) (24, 25). Another important signal at the mast cell-nerve synapse is substance P. Released by both neurons and mast cells, substance P leads to production of prostaglandins and leukotrienes, as well as TNF-a and IL-6 by mast cells (26, 27). Substance P-NK-1 binding primes mast cells to degranulate upon repeated application of lower doses of substance P (28).
Mast cells reside in sentinel locations in the tissue and release a versatile repertoire of mediators (29) including those that interact structurally and functionally with pain-sensing nociceptors (3). Their contributions to pain pathways in the peripheral tissues as well as in central sensitization mechanisms are active areas of research. These investigations will contribute to our improved understanding of mast cell biology and to the design of novel, rational therapies for the treatment and management of pain.
Tijana Martinov and Alyssa Ashbaugh contributed to this entry.
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