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Central Nervous System Mast Cells in Peripheral Inflammatory Nociception

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Central Nervous System Mast Cells in Peripheral Inflammatory Nociception

Dimitris N Xanthos et al. Mol Pain.

Abstract

Background: Functional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. Little is known about the functional role of spinal cord dural mast cells. In this study, we examine their potential involvement in nociception and synaptic plasticity in superficial spinal dorsal horn. Changes of lower spinal cord dura mast cells and their contribution to hyperalgesia are examined in animal models of peripheral neurogenic and non-neurogenic inflammation.

Results: Spinal application of supernatant from activated cultured mast cells induces significant mechanical hyperalgesia and long-term potentiation (LTP) at spinal synapses of C-fibers. Lumbar, thoracic and thalamic preparations are then examined for mast cell number and degranulation status after intraplantar capsaicin and carrageenan. Intradermal capsaicin induces a significant percent increase of lumbar dural mast cells at 3 hours post-administration. Peripheral carrageenan in female rats significantly increases mast cell density in the lumbar dura, but not in thoracic dura or thalamus. Intrathecal administration of the mast cell stabilizer sodium cromoglycate or the spleen tyrosine kinase (Syk) inhibitor BAY-613606 reduce the increased percent degranulation and degranulated cell density of lumbar dural mast cells after capsaicin and carrageenan respectively, without affecting hyperalgesia.

Conclusion: The results suggest that lumbar dural mast cells may be sufficient but are not necessary for capsaicin or carrageenan-induced hyperalgesia.

Figures

Figure 1
Figure 1
Mast cell mediators are sufficient to induce persistent nociception and long-term potentiation. Intrathecally injected supernatant from cultured mast cells activated for 1 hour induces significant mechanical hyperalgesia at 1 day post injection, while supernatant from mast cells activated for 24 hours induces significant mechanical hyperalgesia at 4 hours, 1 day, 2 days, and 4 days post-injection (* = P < 0.05) (A). No significant thermal hyperalgesia is seen (B), although cold allodynia is detected at 4 hours and 1 day post injection of supernatant from mast cells activated for both 1 hour and 24 hours (* = P < 0.05) (C). TNFα, IL-6, and IL-4 are detected in supernatant from 24 hour activated mast cells, and a lower level of IL-6 is detected in supernatant from 1 hour activated mast cells (BD: below detection). Experiment is representative from mast cell supernatant obtained from two independent batches of mast cells that were subsequently used in behavioral and electrophysiology experiments (D). LTP is elicited in 4 out of 6 animals from lumbar spinal application of supernatant of 1-hour stimulated mast cells (E), and in 6 out of 6 animals from lumbar spinal application of supernatant of 24-hour stimulated mast cells (F) (Calibration bars: 100 ms, 0.2 mV).
Figure 2
Figure 2
Mast cell degranulation is increased 3 hours after capsaicin. Mast cells are present in the lumbar dura and can be visualized with toluidine blue staining as mostly granulated with some being degranulated after vehicle treatment (A) or intensively degranulated after Compound 48/80 (B). C-fiber stimulation with capsaicin induces a significant increase in percent mast cell degranulation at 3 hours post-injection in the lumbar dura mater as compared to vehicle (C), but not in the thoracic dura mater (D) (* = P < 0.05). I.p. Compound 48/80 administration induces a significant increased in percent degranulation in both lumbar and thoracic dura mater (* = P < 0.05) (C, D). There are no significant changes in granulated, degranulated, or total mast cell density in neither the lumbar (E), nor the thoracic dura mater (F) after Compound 48/80 or capsaicin administration.
Figure 3
Figure 3
Intrathecally administered mast cell inhibitors reduce mast cell degranulation but not capsaicin hyperalgesia. Intrathecal cromolyn (200 μg) administered prior to intradermal 1% capsaicin (at timepoints shown by ↑) does not reduce mechanical hyperalgesia (A). There is also no effect of intrathecal cromolyn or BAY-613606 pretreatment on mechanical hyperalgesia (B) induced by 0.2% capsaicin. However, both BAY-613606 and cromolyn significantly reduce increased percent mast cell degranulation induced by 1% capsaicin in the lumbar dura mater (C) (* = P < 0.05 as compared to capsaicin alone), but not in the thoracic dura mater (D). BAY-613606, but not cromolyn, further reduces degranulated and total cell density in the lumbar dura mater (E) (# = P < 0.05 as compared to capsaicin + vehicle) but not in thoracic dura mater (F).
Figure 4
Figure 4
Mast cell density is increased in the lumbar dura mater at 24 hours and 72 hours post-carrageenan in female rats. Intraplantar carrageenan does not induce a significant increase in percent degranulation or any changes in total, granulated, or degranulated cell densities in male rats in the lumbar (A, E) or in thoracic (B, G) dura mater. There is no significant increase in percent mast cell degranulation after carrageenan treatment in female rats in the lumbar dura mater (B) or in the thoracic dura mater (D). However, intraplantar carrageenan induces a significant increase in total, granulated and degranulated mast cell densities in the lumbar dura mater at 24 hours post-injection and in degranulated and total mast cell densities at 72 hours post-injection (* = P < 0.05, ** = P < 0.001) (F). 1% carrageenan also induces increased total, granulated and degranulated mast cell densities at 24 hours post-injection in the lumbar dura mater (F). Degranulated cell density is increased in the thoracic dura mater of female rats at 72 hours post-injection (H).
Figure 5
Figure 5
Thalamic mast cell degranulation or density is not changed after carrageenan in neither male nor female rats. There are significant numbers of mast cells in the posterior thalamus which are usually close to blood vessels (examples in A and B). Male and female carrageenan-treated rats do not show differences in percent mast cell degranulation as compared to vehicle, and there are also no significant ipsilateral/contralateral hemisphere differences in percent mast cell degranulation (C, D). Average mast cell number per section is also not significantly different between carrageenan treatments and vehicle in male and female rats, and there are also no significant ipsilateral/contralateral hemisphere differences (E, F).
Figure 6
Figure 6
Effect of intrathecally administered mast cell inhibitors on carrageenan hyperalgesia and mast cell degranulation and density. Intrathecal administration of either cromolyn or BAY-613606 in female rats before and after carrageenan (at timepoints shown by ↑) does not inhibit mechanical hyperalgesia (A), thermal hyperalgesia (B), or cold allodynia (C). However, BAY-613606 significantly reduces the percent mast cell degranulation in lumbar dura mater (D) (** = P < 0.001) but not in the thoracic dura mater (E) of female rats, while both cromolyn and BAY-613606 inhibit the increased degranulated mast cell density induced by carrageenan in female rats in the lumbar dura mater (F) (* = P < 0.05) but not in the thoracic dura mater (G).

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