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The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice
Published on: July 16, 2014
Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and
R J Cady1, J E Denson1, L Q Sullivan1
1Missouri State University, 524 North Boonville Avenue, Springfield, MO 65806, United States.
Abstract:
Sensitization and activation of trigeminal nociceptors is implicated in prevalent and debilitating orofacial pain conditions including temporomandibular joint (TMJ) disorders. Orexins are excitatory neuropeptides that function to regulate many physiological processes and are reported to modulate nociception. To determine the role of orexins in an inflammatory model of trigeminal activation, the effects of a dual orexin receptor antagonist (DORA-12) on levels of proteins that promote peripheral and central sensitization and changes in nocifensive responses were investigated. In adult male Sprague-Dawley rats, mRNA for orexin receptor 1 (OX₁R) and receptor 2 (OX₂R) were detected in trigeminal ganglia and spinal trigeminal nucleus (STN). OX₁R immunoreactivity was localized primarily in neuronal cell bodies in the V3 region of the ganglion and in laminas I-II of the STN. Animals injected bilaterally with complete Freund's adjuvant (CFA) in the TMJ capsule exhibited increased expression of P-p38, P-ERK, and lba1 in trigeminal ganglia and P-ERK and lba1 in the STN at 2 days post injection. However, levels of each of these proteins in rats receiving daily oral DORA-12 were inhibited to near basal levels. Similarly, administration of DORA-12 on days 3 and 4 post CFA injection in the TMJ effectively inhibited the prolonged stimulated expression of protein kinase A, NFkB, and Iba1 in the STN on day 5 post injection. While injection of CFA mediated a nocifensive response to mechanical stimulation of the orofacial region at 2h and 3 and 5 days post injection, treatment with DORA-12 suppressed the nocifensive response on day 5. Somewhat surprisingly, nocifensive responses were again observed on day 10 post CFA stimulation in the absence of daily DORA-12 administration. Our results provide evidence that DORA-12 can inhibit CFA-induced stimulation of trigeminal sensory neurons by inhibiting expression of proteins associated with sensitization of peripheral and central neurons and nociception.
Insights
Dual orexin receptor antagonist (DORA-12) effectively reduced trigeminal nerve activation and orofacial pain in an inflammatory model. This suggests orexin signaling plays a key role in persistent pain conditions.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Trigeminal nociceptor sensitization drives orofacial pain, including temporomandibular joint (TMJ) disorders.
- Orexins, neuropeptides regulating physiological processes, are known to modulate nociception.
Purpose of the Study:
- To investigate the role of orexin signaling in an inflammatory orofacial pain model.
- To evaluate the effects of a dual orexin receptor antagonist (DORA-12) on trigeminal activation and pain responses.
Main Methods:
- Orexin receptor 1 (OX₁R) and 2 (OX₂R) mRNA and OX₁R protein expression were analyzed in rat trigeminal ganglia and spinal trigeminal nucleus (STN).
- Complete Freund's adjuvant (CFA) induced TMJ inflammation in rats.
- DORA-12 was administered orally to assess its impact on inflammatory protein expression (P-p38, P-ERK, Iba1, protein kinase A, NFkB) and nocifensive responses.
Main Results:
- OX₁R and OX₂R were detected in trigeminal pathways; OX₁R was localized in the trigeminal ganglion and STN.
- CFA injection increased sensitization markers (P-p38, P-ERK, Iba1) in trigeminal ganglia and STN.
- DORA-12 treatment significantly inhibited CFA-induced increases in these proteins and suppressed nocifensive responses.
- DORA-12 also inhibited prolonged expression of protein kinase A, NFkB, and Iba1 in the STN.
Conclusions:
- Orexin signaling contributes to inflammatory trigeminal activation and orofacial pain.
- DORA-12 effectively inhibits central and peripheral sensitization pathways involved in orofacial pain.
- Targeting orexin receptors represents a potential therapeutic strategy for managing debilitating orofacial pain conditions.
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