Percutaneous image-guided cryoneurolysis is safe and effective for the management of several well-described syndromes involving neuropathic pain. Additional rigorous prospective study is warranted to further define the efficacy and specific role of these interventions.

The intracellular protein p120 catenin aids in maintenance of cell-cell adhesion by regulating E-cadherin stability in epithelial cells. In an effort to understand the biology of p120 catenin in pancreas development, we ablated p120 catenin in mouse pancreatic progenitor cells, which resulted in deletion of p120 catenin in all epithelial lineages of the developing mouse pancreas: islet, acinar, centroacinar, and ductal. Loss of p120 catenin resulted in formation of dilated epithelial tubules, expansion of ductal epithelia, loss of acinar cells, and the induction of pancreatic inflammation. Aberrant branching morphogenesis and tubulogenesis were also observed. Throughout development, the phenotype became more severe, ultimately resulting in an abnormal pancreas comprised primarily of duct-like epithelium expressing early progenitor markers. In pancreatic tissue lacking p120 catenin, overall epithelial architecture remained intact; however, actin cytoskeleton organization was disrupted, an observation associated with increased cytoplasmic PKCζ. Although we observed reduced expression of adherens junction proteins E-cadherin, β-catenin, and α-catenin, p120 catenin family members p0071, ARVCF, and δ-catenin remained present at cell membranes in homozygous p120f/f pancreases, potentially providing stability for maintenance of epithelial integrity during development. Adult mice homozygous for deletion of p120 catenin displayed dilated main pancreatic ducts, chronic pancreatitis, acinar to ductal metaplasia (ADM), and mucinous metaplasia that resembles PanIN1a. Taken together, our data demonstrate an essential role for p120 catenin in pancreas development.

Cryoneurolysis is the deliberate application of cold temperatures to nerves for therapeutic purposes. The idea of treating pain with this technique is thousands of years old and has evolved over time through the application of surgical techniques, nerve stimulation and/or landmark guidance, and through device development. Recent integration of the interventional radiology skill set to this space has unlocked a myriad of opportunities—primarily through a unique ability to percutaneously access deep structures in the body with accuracy and precision, and the capacity to monitor ablation zones. Understanding of the specific neurohistological process that follows targeted cryoneurolysis leads to new options for treating patients in pain without drugs and opens doors for the potential modification of a wide array of disease states.

Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double-bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about twenty-fold higher μ-affinity than the compound with an Nphenylpropyl substituent (K i = 2 to 450 nM for the examined compounds with various Nsubstituents). Most of the compounds acted unusually as inverse agonists in the [ 35 S]GTP-γ-S functional binding assay using non-dependent cells that stably express the cloned human μ-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent μ-opioid antagonists ((+)−29, K e = 0.17 and (−)−30, K e =0.3) in the [ 35 S]GTP-γ-S functional binding assay. By comparing the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their μ-opioid receptor affinity in terms of the spatial position of N-substituents.