Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington's disease, Alzheimer's, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain.

Components of the short nostril.

BACKGROUND: The short nostril, best visualized on the basilar view, is a multifaceted dysmorphology that requires evaluation beyond that of alar/columellar deformities. While the soft triangle is the key component in short nostril disharmony, the alar rim and cartilaginous structures that border the nostrils play a salient role as well. METHODS: A retrospective review of 200 consecutive rhinoplasties (primary and secondary) examined the specific role of soft triangle excision and other components in the short nostril deformity. Twenty-seven patients underwent soft triangle excision with or without alteration of the other structures influential on nostril length. Of these 27 patients, only three patients required soft triangle excision alone. RESULTS: The distance from the nostril apex to the caudal border of the alar dome was found to be the crucial element in defining the treatment approach for creating nostril length. When this distance was long, excision of the soft triangle lining and approximation of the alar rim to the lining under the dome elevated the nostril apex and elongated the nostril. When the distance between the nostril apex and overlying dome was ideal or short, soft triangle lining removal was not required, and an optimal nostril length was established by repositioning the other components. Raising the dome using transdomal sutures redirected the wide domal arch vertically, narrowing and lengthening the nostril, provided there was no redundancy in the soft triangle. In a similar fashion, interdomal sutures improved both nostril length and inclination. Placement of a columellar strut also elongated the nostril. An alar rim graft, used primarily to correct alar rim retraction and concavity, also elongated the short nostril. CONCLUSIONS: The most important factor in analysis and treatment of the short nostril is the extent of the soft triangle tissue present. Soft triangle lining removal is indicated when the distance from the nostril apex to the caudal dome is excessive. This allows the nostril apex to be pulled anteriorly, thus elongating the nostril. The short nostril often coexists with multiple other abnormalities of the nasal base and tip, mandating a comprehensive approach to address all the deformities encountered. Correction of alar retraction also effectively increases nostril length. Further improvement of asymmetric tips and nostrils can be achieved through unilateral soft triangle lining excision with dome equalization through tip suturing and a subdomal graft.