Pharmacology/Drug Development

The increasing rate of cesarean deliveries warrants obstetric anesthesiologists to deliver high-quality post-cesarean delivery analgesia. The aim of this study was to evaluate the temporal trends in the use of neuraxial morphine for cesarean deliveries and to describe the current postoperative analgesia practices. A retrospective cohort study using nationwide health insurance claims databases was conducted from 2005 to 2020 in Japan. Pregnant women who had undergone cesarean deliveries were included. The annual rate of neuraxial morphine use was extracted and analyzed. Additionally, we explored the patient- and facility-level factors associated with neuraxial morphine use through a multilevel logistic regression analysis. The cohort included 65,208 cesarean delivery cases from 2275 institutions. The prevalence of neuraxial morphine use was 16.0% (95% confidence interval [CI], 15.8-16.3) in the overall cohort. Intrathecal morphine was used in 20.6% (95% CI, 20.2-21.0) of spinal anesthesia cases. The trend in neuraxial morphine use steadily increased from 2005 to 2020. The significant predictors of neuraxial morphine use included spinal anesthesia, recent surgery, large medical facilities, and academic hospitals. Variations in the utilization of postoperative analgesia were observed. Our study described the current trend of neuraxial morphine use and the variation in postoperative analgesia practice in Japan.

Methylmercury (MeHg), an environmental toxicant, is known to cause sensory impairment by inducing neurodegeneration of sensory nervous systems. However, in recent years, it has been revealed that neuropathic pain occurs in the chronic phase of MeHg poisoning, that is, in current Minamata disease patients. Our recent study using Minamata disease model rats demonstrated that MeHg-mediated neurodegeneration in the sensory nervous system may induce inflammatory microglia production in the dorsal horn of the spinal cord and subsequent somatosensory cortical rewiring, leading to neuropathic pain. We hypothesized that inhibition of the Rho-associated coiled coil-forming protein kinase (ROCK) pathway could prevent MeHg-induced neuropathic pain because the ROCK pathway is known to be involved in inducing the production of inflammatory microglia. Here, we showed for the first time that Fasudil, a ROCK inhibitor, can prevent neuropathic pain in Minamata disease model rats. In this model, Fasudil significantly suppressed nerve injury-induced inflammatory microglia production in the dorsal horn of the spinal cord and prevented subsequent somatosensory cortical rewiring. These results suggest that the ROCK pathway is involved in the onset and development of neuropathic pain in the chronic phase of Minamata disease, and that its inhibition is effective in pain prevention.

Eliminating unnecessary pain is an important requirement of performing animal experimentation, including reducing and controlling pain of animals used in pain research. The goal of this study was to refine an adjuvant-induced monoarthritis model in rats by providing analgesia with a transdermal fentanyl solution (TFS). Male and female Sprague-Dawley rats, single- or pair-housed, were injected with 20 μL of complete Freund adjuvant (CFA) into the left ankle joint. CFA-injected rats treated with a single dose of transdermal fentanyl solution (0.33 or 1 mg/kg) were compared with an untreated CFA-injected group and sham groups that received either no treatment or TFS treatment (1 mg/kg) during 72 h. At the tested doses, TFS reduced mechanical hyperalgesia and improved the mobility, stance, rearing, and lameness scores at 6 h after CFA injection. Joint circumferences were not reduced by TFS treatment, and no significant differences were detected between the 2 doses of TFS, or between single- and pair-housed rats. Treatment with TFS did not appear to interfere with model development and characteristics. However, overall, the analgesic effect was transient, and several opioid-related side effects were observed.

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.

Inflammation plays an important role in the development of rheumatoid arthritis (RA). NR4A1 is an anti-inflammatory orphan nuclear receptor involved in protection from inflammatory stimuli in RA. In this study we have explored the anti-inflammatory potential of the FDA-approved drug 9-aminoacridine (9AA) and the natural compound caffeic acid (CA) conjugated to nanomicelles for the treatment of RA. We have synthesized methoxy polyethylene glycol polycaprolactone block copolymer (mPEG–PCL) by ring opening polymerization of ε-caprolactone. Then, we conjugated the hydrophilic caffeic acid (CA) with mPEG–PCL micelles via Steglich esterification and incorporated the 9AA drug. These nanomicelles were formulated by the solvent evaporation method with a size distribution around 190 nm and showed maximum drug loading capacity along with sustained drug release behavior. Furthermore, we tested the therapeutic potential of the formulated 9AA-encapsulated CA-conjugated nanomicelles (9AA-NMs) against an experimental RA model. We observed promising results which showed alleviation of arthritic symptoms by reducing inflammation, joint damage, bone erosion, and swelling. Further, collagen destruction was significantly reduced in articular cartilage, as shown by safranin-O and toluidine blue staining. The protective mechanism might be due to the simultaneous inhibition of NF-κB by 9AA and CA, whereas the activation of NR4A1 by 9AA leads to the suppression of HIF-1α. This combined therapeutic effect of 9AA and CA has enhanced the therapeutic efficacy of 9AA-NM and markedly reduced the severity of inflammatory arthritis. Unlike existing drugs for pain management and with limited efficacy, 9AA-NM exerted a disease-relevant activation/blockade that alleviated inflammation and exhibited marked therapeutic efficacy against RA.

Sensory innervation of the skin is essential for its function, homeostasis and wound healing mechanisms. Thus, to adequately model the cellular microenvironment and function of native skin, in vitro human skin equivalents (hSE) containing a sensory neuron population began to be researched. In this work, we established a fully human three-dimensional (3D) platform of hSE innervated by induced pluripotent stem cell-derived nociceptors neurospheres (hNNs), mimicking the native mode of innervation. Both the hSE and nociceptor population exhibited morphological and phenotypical characteristics resembling their native counterparts, such as epidermal and dermal layer formation and nociceptor marker exhibition, respectively. In the co-culture platform, neurites developed from the hNNs and navigated in 3D to innervate the hSE from a distance. To probe both skin and nociceptor functionality, we applied a clinically available capsaicin patch (Qutenza™) directly over the hSE section and analyzed neuron reaction. Application of the patch caused an exposure time-dependent neurite regression and degeneration. In platforms absent of hSE, axonal degeneration was further increased, highlighting the role of the skin construct as a barrier. In sum, we established an in vitro tool of functional innervated skin with high interest for preclinical research. This article is protected by copyright. All rights reserved.

Repetitive opioid use does not always alleviate basal pain, procedural pain, or both after burn injury. Mitigation of burn injury-site pain can be achieved by GTS-21 stimulation of α7-acetylcholine nicotinic receptors (α7AChRs) and reduced microglia activation in rat. We tested the hypothesis that morphine exaggerates burn injury-site pain and GTS-21 alleviates both morphine-induced aggravated burn injury pain and microglia activation.