Articles: pain-clinics.
-
The development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of G i/o -coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target because of its marked coexpression with transient receptor potential ankyrin 1 (TRPA1), a mediator of noxious mechanotransduction in the bowel. ⋯ Consistent with this mechanism of action, we confirmed that TRPA1-mediated colonic contractions evoked by SP release were abolished by CS pretreatment in a GPR35-dependent manner. Our data demonstrate that GPR35 agonists prevent the activation and sensitisation of colonic nociceptors through the inhibition of TRPA1-mediated SP release. These findings highlight the potential of GPR35 agonists to deliver nonopioid analgesia for the treatment of abdominal pain.
-
Pain profiles (e.g. pro- and anti-nociceptive) can be developed using quantitative sensory testing (QST) but substantial variability exists. This study describes the variability in temporal summation of pain (TSP) and conditioned pain modulation (CPM) in chronic musculoskeletal pain patients, proposes cut-off values, and explores the association with clinical pain intensity. ⋯ This analysis shows that there is variability when assessing TSP and CPM in both pain-free subjects and patients with chronic pain. A cut-off for determining when a person is pain-sensitive is proposed, and data based on this cut-off approach suggest that significantly more patients with osteoarthritis and fibromyalgia are pain-sensitive (i.e. higher TSP and lower CPM) compared to pain-free subjects. This analysis does not find an association between pain sensitivity and clinical pain.
-
Voltage-gated sodium (Na v ) channels present untapped therapeutic value for better and safer pain medications. The Na v 1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. ⋯ In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Na v 1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Na v 1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Na v 1.8 inhibition broadly.
-
Minerva anestesiologica · Feb 2025
Effect of estazolam plus remimazolam on attenuating preoperative anxiety and remifentanil-induced postoperative hyperalgesia in elective gynecological laparoscopic surgery: a randomized clinical trial.
Preoperative anxiety is closely related to opioid-induced hyperalgesia, and high levels of preoperative anxiety have the potential to aggravate opioid-induced hyperalgesia. We aimed to estimate the effect of estazolam, remimazolam, and their combination on preoperative anxiety and opioid-induced hyperalgesia in patients undergoing elective gynecological laparoscopic surgery. ⋯ The preoperative application of estazolam, remimazolam, and their combination can relieve preoperative anxiety and postoperative pain for patients undergoing gynecological laparoscopic surgery. Moreover, the preoperative combination can also significantly reduce postoperative sufentanil consumption.