Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain.

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1 This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8-22 (BAM8-22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8-22 to inhibit high-voltage-activated Ca2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8-22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.

Radiofrequency Ablation in Coccydynia: A Case Series and Comprehensive, Evidence-Based Review.

Objectives: Coccydynia is a condition with a multitude of different causes, characterized by ill-defined management. There are multiple prospective studies, including several controlled trials, that have evaluated conservative therapies. Additionally, a plethora of observational studies have assessed coccygectomy, but few studies have reported results for nonsurgical interventional procedures. In this report, we describe the treatment results of 12 patients who received conventional or pulsed radiofrequency for coccydynia and systematically review the literature on management. Methods: We performed a retrospective data analysis evaluating patients who underwent pulsed or conventional radiofrequency treatment at Johns Hopkins Hospital and Walter Reed National Military Medical Center. A comprehensive literature review was also performed to contextualize these results. Results: The mean age of patients treated was 50.25 years (SD = 11.20 years, range = 32-72 years), with the mean duration of symptoms being 3.6 years (SD = 3.36 years, range 1-10 years). There were 10 males and two females in this cohort. Among patients who received radiofrequency treatment, the average benefit was 55.5% pain relief (SD = 30.33%, range = 0-100%). Those who underwent conventional (vs pulsed radiofrequency) and who received prognostic blocks were more likely to experience a positive outcome. There were two cases of neuritis, which resolved spontaneously after several weeks. Conclusions: Radiofrequency ablation of the sacrococcygeal nerves may serve as a useful treatment option for patients with coccydynia who have failed more conservative measures. Further research into this therapeutic approach and its benefit for coccydynia should incorporate a control group for comparison.