Accepted

Primary afferent neurons of the dorsal root ganglia (DRG) transduce peripheral nociceptive signals and transmit them to the spinal cord. These neurons also mediate analgesic control of the nociceptive inputs, particularly through the μ-opioid receptor (encoded by ). While opioid receptors are found throughout the neuraxis and in the spinal cord tissue itself, intrathecal administration of μ-opioid agonists also acts directly on nociceptive nerve terminals in the dorsal spinal cord resulting in marked analgesia. Additionally, selective chemoaxotomy of cells expressing the TRPV1 channel, a nonselective calcium-permeable ion channel that transduces thermal and inflammatory pain, yields profound pain relief in rats, canines, and humans. However, the relationship between and expressing DRG neurons has not been precisely determined. The present study examines rat DRG neurons using high resolution multiplex fluorescent hybridization to visualize molecular co-expression. Neurons positive for exhibited varying levels of expression for and co-expression of other excitatory and inhibitory ion channels or receptors. A subpopulation of densely labeled + neurons did not co-express . In contrast, a population of less densely labeled + neurons did co-express . This finding suggests that the medium/low expressing neurons represent a specific set of DRG neurons subserving the opponent processes of both transducing and inhibiting nociceptive inputs. Additionally, the medium/low expressing neurons co-expressed other markers implicated in pathological pain states, such as and , which are involved in chemical nociception and cold allodynia, respectively, as well as , whose mutations are implicated in familial episodic pain. Conversely, none of the + neurons co-expressed , which codes for osteopontin, a marker for large diameter proprioceptive neurons, validating that nociception and proprioception are governed by separate neuronal populations. Our findings support the hypothesis that the population of and coexpressing neurons may explain the remarkable efficacy of opioid drugs administered at the level of the DRG-spinal synapse, and that this subpopulation of + neurons is responsible for registering tissue damage.

Mechanical allodynia (pain produced by innocuous stimuli such as touch) is the main symptom of neuropathic pain. Its underlying mechanism remains to be elucidated, but peripheral nerve injury (PNI)-induced malfunction of neuronal circuits in the central nervous system, including the spinal dorsal horn (SDH), is thought to be involved in touch-pain conversion. Here, we found that intra-SDH injection of adeno-associated viral vectors including a prodynorphin promoter (AAV-PdynP) captured a subset of neurons that were mainly located in the superficial laminae, including lamina I, and exhibited mostly inhibitory characteristics. Using transgenic rats that enable optogenetic stimulation of touch-sensing Aβ fibers, we found that the light-evoked paw withdrawal behavior and aversive responses after PNI were attenuated by selective ablation of AAV-PdynP-captured SDH neurons. Notably, the ablation had no effect on withdrawal behavior from von Frey filaments. Furthermore, Aβ fiber stimulation did not excite AAV-PdynP SDH neurons under normal conditions, but after PNI, this induced excitation, possibly due to enhanced Aβ fiber-evoked excitatory synaptic inputs and elevated resting membrane potentials of these neurons. Moreover, the chemogenetic silencing of AAV-PdynP neurons of PNI rats attenuated the Aβ fiber-evoked paw withdrawal behavior and c-FOS expression in superficial SDH neurons. Our findings suggest that PNI renders AAV-PdynP-captured neurons excitable to Aβ fiber stimulation, which selectively contributes to the conversion of Aβ fiber-mediated touch signal to nociceptive. Thus, reducing the excitability of AAV-PdynP-captured neurons may be a new option for the treatment of neuropathic allodynia.

Digital therapeutics (DTx, mobile medical apps, software as a medical device) are rapidly emerging as clinically effective treatments for diverse chronic diseases. For example, the Food and Drug Administration (FDA) has recently authorized a prescription virtual reality (VR) app for treatment of moderate to severe low back pain. The FDA has also approved an adjunct digital therapy in conjunction with buprenorphine for opioid use disorder, further illustrating opportunities to integrate digital therapeutics with pharmacotherapies. There are ongoing needs to disseminate knowledge about advances in digital interventions among health care professionals, policymakers, and the public at large. This mini-review summarizes accumulating clinical evidence of digital interventions delivered virtual reality and mobile apps to improve opioid-based analgesia. We identified relevant randomized controlled trials (RCTs) using Embase and PubMed databases which reported pain scores with a validated pain scale (e.g., visual analog scales, graphic rating scale, numeric rating scale) and use of a digital intervention in conjunction with opiates. Among identified RCTs, the majority of studies reported improved pain scores in the digital intervention group, as compared to "treatment as usual" group. Our work suggests that VR and mobile apps can be used as adjunct digital therapies for pain management. We discuss these findings in the context of how digital health technologies can transform patient-centered pharmacy care.

Urinary tract infections (UTIs) can evoke a rapid host immune response leading to bladder inflammation and epithelial damage. Neuroimmune interactions are critical for regulating immune function in mucosal tissues. Yet the role of nociceptor neurons in bladder host defense has not been well defined. This study aimed to explore the interaction between nociceptor neurons and bladder immune system during UTIs.

Serine proteases are heavily present in the gastrointestinal tract where they are essential in numerous physiological processes. An imbalance in the proteolytic activity is a central mechanism underlying abdominal pain in irritable bowel syndrome (IBS). Therefore, protease inhibitors are emerging as a promising therapeutic tool to manage abdominal pain in this functional gastrointestinal disorder. With this review, we provide an up-to-date overview of the implications of serine proteases in the development of abdominal pain in IBS, along with a critical assessment of the current developments and prospects of protease inhibitors as a therapeutic tool. In particular, we highlight the current knowledge gap concerning the identity of dysregulated serine proteases that are released by the rectal mucosa of IBS patients. Finally, we suggest a workflow with state-of-the-art techniques that will help address the knowledge gap, guiding future research towards the development of more effective and selective protease inhibitors to manage abdominal pain in IBS.

In recent years, there have been an increasing number of studies on trigeminal neuralgia (TN). However, a scientific and comprehensive study of the current situation and trends in the field of TN research is lacking. The purpose of this study is to summarize and visualize the development, research hotspots, and future trends in TN based on a bibliometric approach.

Petasins are the pharmacologically active ingredients of butterbur and of therapeutic benefit in the treatment of migraine and tension headaches. Here, we summarize the pharmacology, safety and clinical efficacy of butterbur in the prevention of migraine attacks and present new data on its mode of action. We review published literature and study reports on the safety and clinical efficacy of the butterbur root extract Petadolex® and report new findings on petasins in dampening nociception by desensitizing calcium-conducting TRP ion channels of primary sensory neurons. Importantly, butterbur diminishes the production of inflammatory mediators by inhibiting activities of cyclooxygenases, lipoxygenases and phospholipase A2 and desensitizes nociception by acting on TRPA1 and TRPPV1 ion channels. It inhibits the release of calcitonin-gene related peptide (CGRP) of meningeal afferents during migraine attacks. We also evaluated the safety of a butterbur root extract in repeated dose studies for up to 6 months. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At supratherapeutic doses, i.e., 45-90-fold MCD, we observed bile duct hyperplasia, and mechanistic studies revealed regulations of solute carriers to likely account for bile duct proliferations. Additionally, liver function tests were performed in cultures of primary human hepatocytes and did not evidence hepatotoxicity at therapeutic butterbur level and with migraine co-medications. Lastly, in randomized, double-blinded and placebo-controlled trials with Petadolex® migraine attack frequency was reduced significantly at 150 mg/day, and no relevant abnormal liver function was reported. Together, butterbur is effective in the prevention of migraine attacks by blocking CGRP signaling.