A novel method for modeling facial allodynia associated with migraine in awake and freely moving rats - PubMed (original) (raw)

A novel method for modeling facial allodynia associated with migraine in awake and freely moving rats

Julie Wieseler et al. J Neurosci Methods. 2010.

Abstract

Migraine is a neurovascular disorder that induces debilitating headaches associated with multiple symptoms including facial allodynia, characterized by heightened responsivity to normally innocuous mechanical stimuli. It is now well accepted that immune activation and immune-derived inflammatory mediators enhance pain responsivity, including the trigeminal system. Nociceptive ("pain" responsive) trigeminal nerves densely innervate the cranial meninges. We have recently proposed that the meninges may serve as a previously unidentified, key interface between the peripheral immune system and the CNS with potential implications for understanding underlying migraine mechanisms. Our focus here is the development of a model for facial allodynia associated with migraine. We developed a model wherein an indwelling catheter is placed between the skull and dura, allowing immunogenic stimuli to be administered over the dura in awake and freely moving rats. Since the catheter does not contact the brain itself, any proinflammatory cytokines induced following manipulation derive from resident or recruited meningeal immune cells. While surgery alone does not alter immune activation markers, TNF or IL6 mRNA and/or protein, it does decrease gene expression and increase protein expression of IL-1 at 4 days after surgery. Using this model we show the induction of facial allodynia in response to supradural administration of either the HIV glycoprotein gp120 or inflammatory soup (bradykinin, histamine, serotonin, and prostaglandin E2), and the induction of hindpaw allodynia in our model after inflammatory soup. This model allows time- and dose-dependent assessment of the relationship between changes in meningeal inflammation and corresponding exaggerated pain behaviors.

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Figures

Figure 1

Figure 1. Photograph of the supradural catheter implantation sites

Troughs are bilaterally drilled in the skull beginning 2-mm from midline. The troughs are approximately 4-mm long, becoming gradually deeper at the more caudal point. At this point the skull is pierced, while leaving the dura intact. The catheters, constructed from PE-10 tubing, are guided by the troughs and gently inserted bilaterally between the skull and dura mater, with the gently sloping troughs allowing the catheter to slip beneath the skull parallel to the dural surface so to avoid piercing the dura. The catheters are marked to indicate when each is inserted 4–6 mm.

Figure 2

Figure 2. Gene and Protein expression for IL-1 are differentially altered in response to surgery

A) IL-1 gene expression was lower compared naïve control tissues. B) IL-1 protein expression was elevated compared to naïve control tissues. Surgery significantly influences the proinflammatory state in the meninges.

Figure 3

Figure 3. Gene expression is altered in response to saline, inflammatory soup and gp120

A) A single application of gp120 (gp120(1)) and double application of gp120 (gp120(2)) significantly up-regulated CD11b gene expression compared to single or double application of saline (saline (1) or saline (2); *), and compared to a single application of inflammatory soup (IS (1); **). B) MHCII expression was also affected, however the post hoc analyses did not reveal further significant differences. The graph suggests that single application of inflammatory soup (IS (1)) or gp120 (gp120(1)) up-regulates MHCII gene expression whereas saline, single or repeated application (saline (1) or saline (2)) does not alter MHCII.

Figure 4

Figure 4. Facial allodynia induced by surgery is resolved 4 days post

Surgery for the placement of bilateral supradural catheters and sham surgery (skin incision with skull scraping) induced facial allodynia immediately following surgery on days 1 and 2. By day 4, behavior among surgery groups and naïve to surgery rats were indistinguishable. * indicates differences compared to naïve.

Figure 5

Figure 5. Mast cells are degranulated 4 days post supradural catheterization

A) Naïve meningeal tissues comparable to those surround the supradural catheter, and B) meningeal tissue surrounding the supradural catheter, stained with mast cell specific stain, toluidine blue.

Figure 6

Figure 6. Development of facial allodynia in rats injected supradurally with gp120

Following baseline (pre-drug) assessment of response to calibrated von Frey filaments, rats received supradural injections of either saline or gp120. Two successive supradural injections of saline produced no reliable changes in behavior of awake and freely moving rats across the timecourse tested. In contrast, two successive supradural injections of gp120, separated by 2 hours, induced facial allodynia at 3 hours after the second injection.

Figure 7

Figure 7. Development of facial allodynia in rats injected supradurally with inflammatory soup (IS)

Following baseline (pre-drug) assessment of response to calibrated von Frey filaments, rats received supradural injections of either saline or IS. Two successive supradural injections of saline (filled circles) produced no reliable changes in the behavior of awake and freely moving rats across the timecourse tested. In contrast, two successive supradural injections of IS, separated by 2 hours, induced facial allodynia at 2 and 4 hours after the second injection.

Figure 8

Figure 8. Development of hind-paw allodynia in rats injected supradurally with inflammatory soup (IS)

Following baseline (pre-drug) assessment of response to calibrated von Frey filaments, rats received 2 successive supradrual injections of saline, 1, or 2 mM IS. Based on facial allodynia time points, hind-paw allodynia was assessed 2 hours post the second injection. IS induced hind-paw allodynia at both 1 and 2 mM concentrations. * indicate differences from saline.

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