A causal role for TRESK loss of function in migraine mechanisms.

The two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability. Furthermore, using CRISPR-Cas9 engineering to correct the F139WfsX2 mutation, we show a reversal of the heightened neuronal excitability, linking the phenotype to the mutation. In contrast we find no change in excitability in induced pluripotent stem cell derived nociceptors with the C110R mutation and preserved TRESK current; thereby confirming that only the frameshift mutation is associated with loss of function and a migraine relevant cellular phenotype. We then demonstrate the importance of TRESK to pain states by showing that the TRESK activator, cloxyquin, can reduce the spontaneous firing of nociceptors in an in vitro human pain model. Using the chronic nitroglycerine rodent migraine model, we demonstrate that mice lacking TRESK develop exaggerated nitroglycerine-induced mechanical and thermal hyperalgesia, and furthermore, show that cloxyquin conversely is able to prevent sensitization. Collectively, our findings provide evidence for a role of TRESK in migraine pathogenesis and its suitability as a therapeutic target.

Evaluation of prognostic factors for return of urinary and defecatory function in cats with sacrocaudal luxation.

OBJECTIVES: The aim of this study was to evaluate outcomes and prognostic factors for cats with sacrocaudal luxation. METHODS: Medical records and radiographs were reviewed for cats with sacrocaudal luxation. Information obtained from the clinical records included signalment, clinical presentation, concurrent traumatic injuries, treatment details, outcome and survival time. Severity of neurological signs was graded from 1 to 5, based on previous grading systems for cats with sacrocaudal luxation. Degree of vertebral displacement was calculated on survey radiographs. Outcomes were collected from serial neurological examinations and telephone interviews. Cats had to be given a minimum of 30 days to regain urinary function to be included in the study. RESULTS: Seventy cats were included. Fifty-five of 61 cats (90%) regained voluntary urinary function. A higher neurological grade was associated with a decreased likelihood (P = 0.01) and longer duration (P = 0.0003) of regaining urinary function. No significant associations were found between urinary outcome and age, sex, anal tone, perineal sensation, tail base sensation, degree of craniocaudal or dorsoventral sacrocaudal displacement, concurrent orthopaedic injury, tail amputation, defecatory function at diagnosis and survival. Cats that regained defecatory function had longer survival times than those that did not recover defecatory function (P = 0.03). Defecatory outcome was not significantly associated with any other variables. CONCLUSIONS AND RELEVANCE: In agreement with previous studies, neurological grade is the most important prognostic indicator for cats with sacrocaudal luxation. Determination of the severity of neurological signs can also aid in advising owners the time frame in which urinary function is expected to return. Faecal incontinence may be a more important prognostic factor than previously suspected.