Neuroscience

The endogenous opioid system plays a crucial role in stress-induced analgesia. Mu-opioid receptors (MORs), one of the major opioid receptors, are expressed widely in subpopulations of cells throughout the CNS. However, the potential roles of MORs expressed in glutamatergic (MORGlut) and γ-aminobutyric acidergic (MORGABA) neurons in stress-induced analgesia remain unclear.

Neuropathic pain is a chronic disorder resulting from damage to the afferent nerve fibers or central pain pathways and is often a complication in pathological conditions such as diabetes, shingles, multiple sclerosis, and stroke. The opioid epidemic has elucidated the need for more efficacious treatments for neuropathic pain. In 2019 alone, nearly 1.6 million people were diagnosed with an opioid use disorder and 48,000 people died from a synthetic opioid overdose.

Here we administered Cre-dependent shRNA to knock-down _Scn8a_ (thus Nav1.6) in Cre-expressing glutamatergic neurons in preBötC and quantified mRNA per glutamatergic neuron. We used adult Vglut2Cre mice (10-14 weeks old) and injected 50 nL of AAVs carrying the shRNA. We used _in situ_ hybridization (RNAscope Fluorescent Assay) to label mRNA of _Scn8a_ and to identify transduced glutamatergic neurons in the preBötC for RNA quantification at 2 and 6 weeks after injection.

In order to characterize these understudied receptors within the liver, we must first understand where they are localized and what activates them. Given the dearth of reliable antibodies, we began by examining expression using RNAscope, a powerful _in situ_ technique that specifically localizes mRNA sequences. GPR108, which has previously been linked to regulation of Toll-Like Receptor signaling, was found within hepatocytes.

Histone deacetylase 6 (HDAC6) is a Class IIb histone deacetylase, which is primarily localized to the cytoplasm and plays an important role in cell structure and dynamism, transcriptional repression, exocytosis and endocytocis. Preclinical evidence has suggested that HDAC6 inhibitors alleviate signs of chemotherapy-induced peripheral neuropathy (CIPN), such as mechanical allodynia. However, no group to our knowledge has investigated the mechanism of action of HDAC6 inhibitors in a severe nerve injury model, which has a different pathophysiology than milder models such as CIPN.

The renin-angiotensin system (RAS) has been implicated in stress-related disorders, however the central mechanisms responsible for this remains unknown. The locus coeruleus (LC), a major noradrenergic nucleus of the brain, plays a critical role in modulating anxiety-like behaviors. The LC has also been previously shown to express angiotensinogen (AGT), the pre-cursor for angiotensin, as well as strong expression of angiotensin II receptors, but its role in stress-related disorders has not been examined.

The nucleus accumbens (NAc) is the key area of the reward circuit, but its heterogeneity has been poorly studied. Using single-cell RNA sequencing, we revealed a subcluster of GABAergic neurons characterized by cell division cycle 20 (Cdc20) mRNA expression in the NAc of adult rats. We studied the coexpression of Cdc20 and Gad1 mRNA in the NAc neurons of adult rats and assessed Cdc20 protein expression in the NAc during rat development.

Neuropathic pain is a chronic condition which can arise following damage to the somatosensory system and often involves both hyperalgesia and allodynia. The molecular mechanisms of neuropathic pain remain incompletely understood but require enduring alterations in specific gene programs and protein synthesis affecting neuronal signaling and excitability. We investigate non-coding RNA and RNA-binding protein regulatory pathways in impacting hyperalgesia and neuropathic pain using the mouse spared nerve injury model.

Keratinocytes are closely juxtaposed to cutaneous nerve terminals, enabling communication between keratinocytes and cutaneous nerves. We investigated potential mechanisms that mediate this communication. We genetically expressed stimulatory DREADDs (hM3Dq) into K14 basal keratinocytes (K14) in mice as a tool for mimicking the activation of Gq-linked G protein-coupled receptors (GPCRs) in K14 expressing cells.

Chronic pain is exceedingly prevalent in individuals over 65 years of age. Still, it is under-managed due in large part to a dearth of knowledge regarding the suitable dosing of opioids for chronic pain management. We have shown that advanced age and sex alter morphine modulation of persistent inflammatory pain (induced by intraplantar Complete Freund's adjuvant (CFA)). Specifically, morphine potency was highest in adult male rats (2mos), with a 2-fold rightward shift in the dose-response curve for aged males (18mos) and females regardless of age.