Pharmacology/Drug Development

Our recent study revealed that spinal electromagnetic stimulation (sEMS) applied at low (0.2Hz) frequencies may improve diminished transmission in damaged spinal cord in spinal cord injured (SCI) rats. We have recently begun a pilot study investigating the effects of sEMS in non-injured and SCI humans. One unexpected result was the reduction of chronic low back pain (CLBP), reported by some patients following sEMS treatment. Chronic low back pain is one of the main causes of disability affecting the general population. Opioids are the most common drugs prescribed to US adults with CLBP. To optimize parameters for sEMS for pain treatment, in this study we used the SCI animal model and examined effects of sEMS applied at lumbosacral level on parameters and frequency-dependent depression (FDD) of Hoffmann H-reflex responses, known as common neurophysiological measures for evaluation of sensorimotor condition and plasticity in humans. We have also examined the interactive effects of sEMS and the opiate partial agonist Buprenorphine on the parameters of H-reflex in naïve and SCI rats. Consistent with previous reports, chronic SCI resulted in a marked decrease of threshold intensity required to evoke H-reflex and a lesser rate of FDD of the H-response in adult rats. Our current study revealed the optimum parameters of spinal EMS for best recovery of the properties of the H-reflex in chronic SCI animals. Here we demonstrate that electro-magnetic stimulation applied at spinal L4-L5 level with a pulsed mode (pulse at 20 Hz frequency for 5 sec with 25 sec break between pulses, total 40 trains for 20 minutes; PSEMS) reversed effects of SCI on key parameters of H-reflex: i.e. (1) restored the threshold intensity of electric current applied at tibial nerve to evoke the H-reflex and (2) recovered FDD properties of the H-reflex in SCI rats. Importantly, subcutaneous injections of Buprenorphine, prior to PSEMS administration, abolished the ability of PSEMS to recover both threshold intensity and FDD of the H-reflex in chronic SCI animals. These results suggest that a semi-synthetic opioid Buprenorphine and PSEMS might share common sites of action. We thus conclude that PSEMS might carry potential as a non-invasive treatment approach for chronic low back pain.

Osteoarthritis (OA) is a highly prevalent human degenerative joint disorder that has long plagued patients. Glucocorticoid injection into the intra-articular (IA) cavity provides potential short-term analgesia and anti-inflammatory effects, but long-term IA injections cause loss of cartilage. Synovial mesenchymal stem cells (MSCs) reportedly promote cartilage proliferation and increase cartilage content.

The analgesic efficacy of morphine can be affected by a variety of factors. Our previous studies demonstrated that chemokine (CXC motif) ligand 10 (CXCL10) could induce algesia directly and attenuate the analgesic effect produced by a single dose of morphine. However, the underlying mechanism remains unclear. In the present study, we aimed to further investigate the mechanism of CXCL10-mediated inhibition on morphine analgesic effect. According to our findings, recombinant CXCL10 protein (rmCXCL10) could increase the phosphorylation of serine-threonine kinase AKT reduced by morphine in spinal cord. Blocking AKT activation by phosphoinositide 3-kinase (PI3K) inhibitor could effectively attenuate CXCL10-induced algesia, and reverse the decrease of paw withdrawal thresholds caused by the co-administration of morphine and rmCXCL10. Furthermore, rmCXCL10 could enhance the spinal expression of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, which could be blocked by PI3K inhibitor. In summary, these findings suggest that PI3K-AKT signaling pathway mediates the effect of CXCL10 on the regulation of morphine analgesia and the release of cytokines in spinal cord. Our study provides a new insight into the mechanism of chemokine-relative pain regulation.

Fremanezumab, a fully humanised monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy as a preventive treatment for adults with episodic migraine (EM) or chronic migraine (CM) and inadequate response to 2-4 prior preventive treatment classes in the phase 3b FOCUS study. In this post-hoc analysis, we evaluated efficacy and effects on quality-of-life outcomes for fremanezumab in subgroups of patients with and without aura or similar neurological symptoms, here referred to as migraine with or without associated neurological dysfunction.

This post hoc subgroup analysis evaluated the efficacy and safety of eptinezumab for migraine prevention in patients with migraine and self-reported aura.

We aimed to provide real-world data on the effectiveness of an anti-calcitonin gene-related peptide monoclonal antibody administered for treating migraine in Korean patients.

Combinational utilization of intravenous non-steroidal anti-inflammatory drugs (NSAIDs) with opium analgesic is an effective alternative modality for pain control after surgery. This regimen is known for reducing the risk of addiction induced by opium analgesic. However, current intravenous NSAIDs have solubility problems, limiting their clinical applications. Although loxoprofen exhibits strong anti-inflammatory and analgesic activities with relatively low ulcerogenicity, its relatively low bioavailability makes it not an ideal drug candidate for intravenous injection. We selected the bioactive metabolite (6) of loxoprofen as a candidate and developed a new intravenous NSAID, HR1405-01. This metabolite exhibited significantly stronger anti-inflammatory and analgesic activities than parecoxib sodium injection or ibuprofen injection. The excellent potency and solubility of HR1405-01 allowed the avoidance of utilization of cosolvent in the formulation, resulting in fewer side effects and a better safety profile. Therefore, HR1405-01 might be a promising candidate for the development of a new intravenous NSAID.

The "nociplastic pain," a recently proposed novel mechanistic pain descriptor, is defined as pain occurring through altered nociception without nociceptor activation and nerve injury. Nociplastic pain is often characterized by widespread pain sensitization (WSP) in multiple body regions (Fitzcharles et al., 2021). As many patients with primary chronic pain would have nociplastic backgrounds, developing appropriate methods to evaluate drug effects against nociplastic pain in animal model is in great demand. Using two rat models with the WSP involving central amygdala (CeA) activation by orofacial inflammation or direct chemogenetic activation (Sugimoto et al., 2021), we examined whether widely used analgesics, acetaminophen (AcAph), pregabalin (PGB), and duloxetine (DLX) could attenuate the WSP. AcAph (100 or 200 mg/kg, i.p.) significantly elevated 50%-paw withdrawal threshold (PWT), which had been lowered significantly by upper lip injection of formalin, or systemic injection of clozapine-N-oxide in the rats with excitatory designer receptors (hM3Dq) expressed in the right CeA. This effect lasted for > ∼4 h. PGB (30 mg/kg, i.p.) also significantly counteracted the lowered PWT in rats with orofacial formalin injection for >∼6 h. DLX was ineffective on the WSP. Based on these results, we propose that these preclinical models could be used to evaluate drug effects for primary chronic pain. We conclude that the widely used pain killers, AcAph and PGB, also relieve nociplastic widespread sensitization in the absence of ongoing nociceptor activation and nerve injury.