Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC) of the infraorbital nerve

Ma, Fei; Zhang, Liping; Lyons, Danielle N.; Westlund, Karin N.

doi:10.1186/1756-6606-5-44

Cited by 56 publications

(73 citation statements)

References 37 publications

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“…Previous studies have reported that PPARγ deficient mice are more vulnerable to inflammatory diseases 50–52 . In our previous study 35 , we demonstrated microglial activation in the trigeminal dorsal horn of mice with TIC nerve injury. Therefore, one possible reason for the increase in PPARγ immunoreactivity observed in the mice with TIC injury could be the inflammatory response occurring in the trigeminal dorsal horn.…”

Section: Discussionmentioning

confidence: 77%

“…The aim of this study is to determine the role of PPARγ in trigeminal neuropathic pain utilizing our novel mouse trigeminal inflammatory compression (TIC) injury model 35 . Our findings are that 1) the immunoreactivity for PPARγ is increased in spVc at 3 weeks in mice with TIC injury and 2) PIO attenuates trigeminal TIC nerve injury related pain dependent on PPARγ activation.…”

Section: Introductionmentioning

confidence: 99%

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PPARγ Agonists Attenuate Trigeminal Neuropathic Pain

Lyons¹,

Zhang²,

Danaher

et al. 2017

The Clinical Journal of Pain

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The aim of this study is to investigate the role of peroxisome proliferator-activated receptor-gamma isoform (PPARγ), in trigeminal neuropathic pain utilizing a novel mouse trigeminal inflammatory compression (TIC) injury model. The study determined that the PPARγ nuclear receptor plays a significant role in trigeminal nociception transmission, evidenced by: 1) Intense PPARγ immunoreactivity is expressed 3 weeks after TIC nerve injury in the spinal trigeminal nucleus caudalis (spV), the termination site of trigeminal nociceptive nerve fibers. 2) Systemic administration of a PPARγ agonist, pioglitazone (PIO), attenuates whisker pad mechanical allodynia at doses of 300 mg/kg i.p. and 600 mg/kg p.o. 3) Administration of a PPARγ antagonist, GW9662 (30 mg/kg i.p.), prior to providing the optimal dose of PIO (300 mg/kg i.p.) blocked the analgesic effect of PIO. This is the first study localizing PPARγ immunoreactivity throughout the brainstem trigeminal spinal trigeminal nucleus caudalis (spV) and its increase three weeks after TIC nerve injury. This is also the first study to demonstrate that activation of PPARγ attenuates trigeminal hypersensitivity in the mouse TIC nerve injury model. The findings presented here suggest the possibility of utilizing the FDA approved diabetic treatment drug, PIO, as a new therapeutic that targets PPARγ for treatment of patients suffering from orofacial neuropathic pain.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

PPARγ Agonists Attenuate Trigeminal Neuropathic Pain

Lyons¹,

Zhang²,

Danaher

et al. 2017

The Clinical Journal of Pain

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“…Similar to mechanisms proposed in that study, the contralateral microglial activation in the present study is likely mediated by crosstalk through the transmedian neurological pathways crossing in the trigeminal nuclear complex since microglia have CGRP receptors (Pfaller and Arvidsson, 1988; Edvinsson et al, 1989). We have observed inflammatory cells in the dissected nerve near the TIC insult at 10 weeks (Ma et al, 2012). The systemic inflammatory reaction to an initial injury and activation of the so called “neuro-immune axis” is modulated by the nucleus solitarius receiving vagal innervation (dorsal vagal complex) (Watkins et al, 1995; Tracey, 2002).…”

Section: Discussionmentioning

confidence: 92%

“…We developed a mouse model of continuous, chronic facial pain induced by inserting chromic gut suture under the infraorbital nerve to produce slight compression and chemical irritation. The histology confirmed mild axonal trauma, inflammation, and disruption of myelin were present among axons immediately adjacent to the suture (Ma et al, 2012). …”

Section: Introductionmentioning

confidence: 82%

“…The infraorbital nerve was located ~5 mm deep in the orbital cavity lying within the infraorbital fissure. The infraorbital nerve was dissected free from the bone and a 2-mm length of chromic gut suture (6–0) was inserted between the infraorbital nerve and the maxillary bone as described previously (Ma et al, 2012). The nerve was not dissected in the surgical sham mice.…”

Section: Methodsmentioning

confidence: 99%

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Dysregulated TNFα promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity

Zhang

Mashni

et al. 2015

Neuroscience

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Background: Tumor necrosis factor alpha (TNFα) is increased in patients with headache, neuropathic pain, periodontal and temporomandibular disease. This study and others have utilized TNF receptor 1/2 (TNFR1/2) knockout (KO) animals to investigate the effect of TNFα dysregulation in generation and maintenance of chronic neuropathic pain. The present study determined the impact of TNFα dysregulation in a trigeminal inflammatory compression (TIC) nerve injury model comparing wild-type (WT) and TNFR1/2 KO mice. Methods: Chromic gut suture was inserted adjacent to the infraorbital nerve to induce the TIC model mechanical hypersensitivity. Cytokine proteome profiles demonstrated serology, and morphology explored microglial activation in trigeminal nucleus 10 weeks post. Results: TIC injury induced ipsilateral whisker pad mechanical allodynia persisting throughout the 10-week study in both TNFR1/2 KO and WT mice. Delayed mechanical allodynia developed on the contralateral whisker pad in TNFR1/2 KO mice but not in WT mice. Proteomic profiling 10 weeks after chronic TIC injury revealed TNFα, interleukin-1alpha (IL-1α), interleukin-5 (IL-5), interleukin-23 (IL-23), macrophage inflammatory MIP-1β(MIP-1β), and granulocyte–macrophage colony-stimulating factor (GM-CSF) were increased more than 2-fold in TNFR1/2 KO mice compared to WT mice with TIC. Bilateral microglial activation in spinal trigeminal nucleus was detected only in TNFR1/2 KO mice. p38 mitogen-activated protein kinase (MAPK) inhibitor and microglial inhibitor minocycline reduced hypersensitivity. Conclusions: The results suggest the dysregulated serum cytokine proteome profile and bilateral spinal trigeminal nucleus microglial activation are contributory to the bilateral mechanical hypersensitization in this chronic trigeminal neuropathic pain model in the mice with TNFα dysregulation. Data support involvement of both neurogenic and humoral influences in chronic neuropathic pain.

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Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain

Strahan

Walker

Montgomery

et al. 2016

Developmental Neurobiology

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Minocycline, an antibiotic of the tetracycline family, inhibits microglia in many paradigms, and is among the most commonly used tools for examining the role of microglia in physiological processes. Microglia may play an active role in triggering developmental neuronal cell death, although findings have been contradictory. To determine whether microglia influence developmental cell death, we treated perinatal mice with minocycline (45 mg/kg) and quantified effects on dying cells and microglial labeling using immunohistochemistry for activated caspase-3 (AC3) and ionized calcium-binding adapter molecule 1 (Iba1), respectively. Contrary to our expectations, minocycline treatment from embryonic day 18 to postnatal day (P)1 caused a >10-fold increase in cell death 8 h after the last injection in all brain regions examined, including the primary sensory cortex (S1), septum, hippocampus and hypothalamus. Iba1 labeling was also increased in most regions. Similar effects, although of smaller magnitude, were seen when treatment was delayed to P3-P5. Minocycline treatment from P3-P5 also decreased overall cell number in the septum at weaning, suggesting lasting effects of the neonatal exposure. When administered at lower doses (4.5 or 22.5 mg/kg), or at the same dose one week later (P10-P12), minocycline no longer increased microglial markers or cell death. Taken together, the most commonly used microglial “inhibitor” increases cell death and Iba1 labeling in the neonatal mouse brain. Minocycline is used clinically in infant and pediatric populations; caution is warrented when using minocycline in developing animals, or extrapolating the effects of this drug across ages.

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Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC) of the infraorbital nerve

Cited by 56 publications

References 37 publications

PPARγ Agonists Attenuate Trigeminal Neuropathic Pain

PPARγ Agonists Attenuate Trigeminal Neuropathic Pain

Dysregulated TNFα promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity

Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain

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