Mast cell degranulation distinctly activates trigemino-cervical and lumbosacral pain pathways and elicits widespread tactile pain hypersensitivity

Abstract

Mast cells (MCs) are tissue resident immune cells that participate in a variety of allergic and other inflammatory conditions. In most tissues, MCs are found in close proximity to nerve endings of primary afferent neurons that signal pain (i.e. nociceptors). Activation of MCs causes the release of a plethora of mediators that can activate these nociceptors and promote pain. Although MCs are ubiquitous, conditions associated with systemic MC activation give rise primarily to two major types of pain, headache and visceral pain. In this study we therefore examined the extent to which systemic MC degranulation induced by intraperitoneal administration of the MC secretagogue compound 48/80 activates pain pathways that originate in different parts of the body and studied whether this action can lead to development of behavioral pain hypersensitivity. Using c-fos expression as a marker of central nervous system neural activation, we found that intraperitoneal administration of 48/80 leads to the activation of dorsal horn neurons at two specific levels of the spinal cord; one responsible for processing cranial pain, at the medullary/C2 level, and one that processes pelvic visceral pain, at the caudal lumbar/rostral sacral level (L6-S2). Using behavioral sensory testing, we found that this nociceptive activation is associated with development of widespread tactile pain hypersensitivity within and outside the body regions corresponding to the activated spinal levels. Our data provide a neural basis for understanding the primacy of headache and visceral pain in conditions that involve systemic MC degranulation. Our data further suggest that MC activation may lead to widespread tactile pain hypersensitivity.

Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice

“…Thus, either the intensity of response evoked by histamine released from C48/80 was higher than exogenous histamine when paralleled by the low availability of H2S released from GYY4137 in situ on the peripheral afferent neurons or it is possibly that C48/80 produces scratching behavior that somehow depends on functional changes evoked by direct activation of pruriceptors. While direct excitatory effects of C48/80 on dorsal root ganglion (DRG), enteric neurons and visceral afferents can occur independently of mast cell activation [54], other works show that the mechanism involved in C48/80-induced nociception is mediated by a cascade activation that starts after mast cell activation, including the release of mediators that can activate these nociceptors and promote pain [55].…”

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

“…16,52 The initial release of inflammatory mediators, such as cytokines, prostaglandins, NO, bradykinins, and histamines, are hypothesized to sensitize trigeminal pain neurons leading to development of chronic headache post-TBI. 8,9,[14][15][16]53 Localized release of inflammatory molecules may lower the threshold for activation of meningeal nociceptors and, as a result, sensitize them to activation by a lesser degree of vessel dilatation. 13,53 Proinflammatory cytokines interleukin 1 beta (IL-1b), and tumor necrosis factor alpha (TNF-a) have been shown to stimulate prostaglandins postinjury.…”

“…8,9,[14][15][16]53 Localized release of inflammatory molecules may lower the threshold for activation of meningeal nociceptors and, as a result, sensitize them to activation by a lesser degree of vessel dilatation. 13,53 Proinflammatory cytokines interleukin 1 beta (IL-1b), and tumor necrosis factor alpha (TNF-a) have been shown to stimulate prostaglandins postinjury. [54][55][56][57] Prostaglandin E2 stimulates neuronal excitability, triggers the trigeminal ganglia neurons to release CGRP, and, in turn, signals pain.…”

Mast cell activation contributes to sickle cell pathobiology and pain in mice

“…25,26 We therefore examined the contribution of mast cell activation to hyperalgesia and hypoxia reperfusion injuryinduced pain by simulating VOC in sickle and control mice. Five days of treatment with imatinib, but not CS, reduced deep-tissue ( Figure 4A), mechanical ( Figure 4B), and heat ( Figure 4C) hyperalgesia in sickle mice.…”