Chemogenetic Modulation of Posterior Insula CaMKIIa Neurons Alters Pain and Thermoregulation.

The posterior insular cortex (PIC) is well positioned to perform somatosensory-limbic integration; yet, the function of neuronal subsets within the PIC in processing the sensory and affective dimensions of pain remains unclear. Here, we employ bidirectional chemogenetic modulation to characterize the function of PIC CaMKIIa-expressing excitatory neurons in a comprehensive array of sensory, affective, and thermoregulatory behaviors. Excitatory pyramidal neurons in the PIC were found to be sensitized under inflammatory pain conditions.

A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression.

Maladaptive changes of nerve injury-associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury-specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury.

Cannabinoid Receptor 1 Expression in Human Dorsal Root Ganglia and CB13-Induced Bidirectional Modulation of Sensory Neuron Activity.

Cannabinoid receptors have been identified as potential targets for analgesia from studies on animal physiology and behavior, and from human clinical trials. Here, we sought to improve translational understanding of the mechanisms of cannabinoid-mediated peripheral analgesia. Human lumbar dorsal root ganglia were rapidly recovered from organ donors to perform physiological and anatomical investigations into the potential for cannabinoids to mediate analgesia at the level of the peripheral nervous system.

Skin-Nerve Co-Culture Systems for Disease Modeling and Drug Discovery.

Prominent clinical problems related to the skin-nerve interface include barrier dysfunction and erythema, but it is the symptoms of pain and itch that most often lead patients to seek medical treatment. Tissue-engineered innervated skin models provide an excellent solution for studying the mechanisms underlying neurocutaneous disorders for drug screening, and cutaneous device development. Innervated skin substitutes provide solutions beyond traditional monolayer cultures and have advantages that make them preferable to animal studies for certain applications, such as measuring somatosensory transduction.

Mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy.

Aims: Duchenne muscular dystrophy (DMD) is an X-linked inherited disease due to dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected patients lose ambulation by age 12 and usually die in the second to third decades of life from cardiac and respiratory failure. Symptomatic treatment includes the use of anti-inflammatory corticosteroids, which are associated with side effects including weight gain, osteoporosis, and increased risk of cardiovascular disease.

Group II metabotropic glutamate receptor expressing neurons in anterior cingulate cortex become sensitized after inflammatory and neuropathic pain.

The anterior cingulate cortex is a limbic region associated with the emotional processing of pain. How neuropathic and inflammatory pain models alter the neurophysiology of specific subsets of neurons in the anterior cingulate cortex remains incompletely understood. Here, we used a :tdtomato reporter mouse line to identify a population of pyramidal neurons selectively localized to layer II/III of the murine anterior cingulate cortex.

Immature murine hippocampal neurones do not develop long-term structural changes after a single isoflurane exposure.

Background: Studies in developing animals show that a clinically relevant anaesthesia exposure increases neuronal death and alters brain structure. In the hippocampal dentate gyrus, the anaesthetic isoflurane induces selective apoptosis among roughly 10% of 2-week-old hippocampal granule cells in 21-day-old mice. In this work, we queried whether the 90% of granule cells surviving the exposure might be 'injured' and integrate abnormally into the brain.

Mineralocorticoid Receptor Antagonists in Muscular Dystrophy Mice During Aging and Exercise.

Background: Mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors have shown preclinical efficacy for both skeletal and cardiac muscle outcomes in young sedentary dystrophin-deficient mdx mice also haploinsufficient for utrophin, a Duchenne muscular dystrophy (DMD) model. The mdx genotypic DMD model has mild pathology, making non-curative therapeutic effects difficult to distinguish at baseline. Since the cardiac benefit of mineralocorticoid receptor antagonists has been translated to DMD patients, it is important to optimize potential advantages for skeletal muscle by further defining efficacy parameters.

Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.

Background: Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor.

Objective: The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril.