Pharmacology/Drug Development

Inflammatory arthritis is the most prevalent chronic inflammatory disease worldwide. The pathology of the disease is characterized by increased inflammation and oxidative stress, which leads to chronic pain and functional loss in the joints. Conventional anti-arthritic drugs used to relieve pain and other arthritic symptoms often cause severe side effects. α-bisabolol (BIS) is a sesquiterpene that exhibits high anti-inflammatory potential and a significant antinociceptive effect. This study evaluates the anti-arthritic, anti-inflammatory and antihyperalgesic effects of BIS alone and in a β-cyclodextrin (βCD/BIS) inclusion complex in a CFA-induced arthritis model. Following the intra-articular administration of CFA, male mice were treated with vehicle, BIS and βCD/BIS (50 mg/kg, p.o.) or a positive control and pain-related behaviors, knee edema and inflammatory and oxidative parameters were evaluated on days 4, 11, 18 and/or 25. Ours findings shows that the oral administration of BIS and βCD/BIS significantly attenuated spontaneous pain-like behaviors, mechanical hyperalgesia, grip strength deficit and knee edema induced by repeated injections of CFA, reducing the joint pain and functional disability associated with arthritis. BIS and βCD/BIS also inhibited the generation of inflammatory and oxidative markers in the knee and blocked MAPK in the spinal cord. In addition, ours results also showed that the incorporation of BIS in cyclodextrin as a drug delivery system improved the pharmacological profile of this substance. Therefore, these results contribute to the pharmacological knowledge of BIS and demonstrated that this terpene appears to be able to mitigate deleterious symptoms of arthritis.

Trigeminal neuralgia (TN) is a neuropathic pain that occurs in branches of the trigeminal nerve. MicroRNAs (miRNAs) have been considered key mediators of neuropathic pain. This study was aimed to elucidate the pathophysiological function and mechanisms of miR-223-3p in mouse models of TN.

Lumbar epidural is the gold standard for labour analgesia. Low concentrations of local anaesthetic are recommended. This network meta-analysis investigated whether further reducing the concentration of local anaesthetic can improve maternal and neonatal outcomes without compromising analgesia. We conducted a systematic search of relevant databases for randomised controlled trials comparing high (>0.1%), low (>0.08% to ≤0.1%) or ultra-low (≤0.08%) concentration local anaesthetic (bupivacaine or equivalent) for labour epidural. Outcomes included mode of delivery, duration of labour and maternal/neonatal outcomes. Bayesian network meta-analysis with random-effects modelling was used to calculate odds ratios or weighted mean differences and 95% credible intervals. A total of 32 studies met inclusion criteria (3665 women). The total dose of local anaesthetic received increased as the concentration increased; ultra-low compared with low (weighted mean difference -14.96 mg, 95% credible interval [-28.38 to -1.00]) and low compared with high groups (weighted mean difference -14.99 [-28.79 to -2.04]), though there was no difference in the number of rescue top-ups administered between the groups. Compared with high concentration, ultra-low concentration local anaesthetic was associated with increased likelihood of spontaneous vaginal delivery (OR 1.46 [1.18 to 1.86]), reduced motor block (Bromage score >0; OR 0.32 [0.18 to 0.54]) and reduced duration of second stage of labour (weighted mean difference -13.02 min [-21.54 to -4.77]). Compared with low, ultra-low concentration local anaesthetic had similar estimates for duration of second stage of labour (weighted mean difference -1.92 min [-14.35 to 10.20]); spontaneous vaginal delivery (OR 1.07 [0.75 to 1.56]; assisted vaginal delivery (OR 1.35 [0.75 to 2.26]); caesarean section (OR 0.76 [0.49 to 1.22]); pain (scale 1-100, weighted mean difference -5.44 [-16.75 to 5.93]); and maternal satisfaction. Although a lower risk of an Apgar score < 7 at 1 min (OR 0.43 [0.15 to 0.79]) was reported for ultra-low compared with low concentration, this was not sustained at 5 min (OR 0.12 [0.00 to 2.10]). Ultra-low concentration local anaesthetic for labour epidural achieves similar or better maternal and neonatal outcomes as low and high concentration, but with reduced local anaesthetic consumption.

Existing pharmacotherapies acting on the opioid receptor system have been extensively used to treat chronic pain and addictive disorders. Nevertheless, the adverse side effects associated with opioid therapy underscore the need for concerted measures to develop safer analgesics. A promising avenue of research stems from the characterization of a sodium-dependent allosteric regulation site housed within the delta-opioid receptor and several other G protein-coupled receptors (GPCRs), thereby revealing the presence of a cluster of sodium and water molecules lodged in a cavity thought to be present only in the inactive conformation of the receptor. Studies into the structure-function relationship of said pocket demonstrated its critical involvement in the functional control of GPCR signaling. While the sodium pocket has been proposed to be present in the majority of class A GPCRs, the shape of this allosteric cavity appears to have significant structural variation among crystallographically solved GPCRs, making this site optimal for the design of new allosteric modulators that will be selective for opioid receptors. The size of the sodium pocket supports the accommodation of small molecules, and it has been speculated that promiscuous amiloride and 5'-substituted amiloride-related derivatives could target this cavity within many GPCRs, including opioid receptors. Using pharmacological approaches, we have described the selectivities of 5'-substituted amiloride-related derivatives, as well as the hitherto undescribed activity of the NHE1 inhibitor zoniporide toward class A GPCRs. Our investigations into the structural features of the delta-opioid receptor and its ensuing signaling activities suggest a bitopic mode of overlapping interactions involving the orthosteric site and the juxtaposed Na pocket, but only at the active or partially active opioid receptor.

The brain mechanism of inflammatory pain is an understudied area of research, particularly concerning the descending pain modulatory system. The G protein-coupled receptor 55 (GPR55) is a lysophosphatidylinositol-sensitive receptor that has also been involved in cannabinoid signaling. It is widely expressed throughout the central nervous system, including the periaqueductal gray (PAG), a brainstem area and key element of the descending pain modulatory system. In this study, we used behavioral, stereotaxic injections, pharmacological tools, and two inflammatory pain models (formalin and carrageenan) to determine if GPR55 in the PAG plays a role in the pain associated with inflammation in rats. It was found that the blockade of GPR55 action in PAG can drive the descending pain modulatory system to mitigate inflammatory pain. These data show that GPR55 plays a role in the descending pain modulatory system in inflammatory pain.

To establish the role of inflammation in bortezomib induced peripheral neuropathy (BIPN).

5-hydroxytryptamine receptor 5A (5-HT) belongs to the 5-HT receptor family and signals through the G protein. It is involved in nervous system regulation and an attractive target for the treatment of psychosis, depression, schizophrenia, and neuropathic pain. 5-HT is the only G-coupled 5-HT receptor subtype lacking a high-resolution structure, which hampers the mechanistic understanding of ligand binding and G coupling for 5-HT. Here we report a cryo-electron microscopy structure of the 5-HT-G complex bound to 5-Carboxamidotryptamine (5-CT). Combined with functional analysis, this structure reveals the 5-CT recognition mechanism and identifies the receptor residue at 6.55 as a determinant of the 5-CT selectivity for G-coupled 5-HT receptors. In addition, 5-HT shows an overall conserved G protein coupling mode compared with other G-coupled 5-HT receptors. These findings provide comprehensive insights into the ligand binding and G protein coupling of G-coupled 5-HT receptors and offer a template for the design of 5-HT-selective drugs.

Mechanical stress plays a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). The mechanosensitive Piezo1 ion channel can sense the changes in mechanical stress and convert the mechanical signals into chemical signals. This study aims to investigate the effect of Piezo1 on the mechanical stress-induced IVDD and explore the possible mechanism.