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Several functional neuroimaging studies on healthy controls and patients with migraine with aura have shown that the activation of functional networks during visual stimulation is not restricted to the striate system, but also includes several extrastriate networks.
Learn More >Although nonsteroidal anti-inflammatory drugs (NSAIDs) are medicines that are widely used to relieve pain, reduce inflammation, and bring down high temperature, literature confirmed that they still have harmful side effects. Most of their side effects are in the digestive system due to the carboxylic group. As naproxen is one of the NSAIDs, in this work, we try to mask the carboxylic group in naproxen with a relatively safe functional group. So, herein, we report the synthesis of new naproxen-based hydrazones derivatives, namely, (E)-N'-1-(4-chlorophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propane hydrazide (4a) and (E)-N'-(4-hydroxybenzylidene)-2-(6-methoxynaphthalen-2-yl)propane hydrazide ethanol solvate (4b). The compounds were confirmed by X-ray diffraction studies. Hirshfeld surface analyses and energy frameworks of 4a and 4b have been carried out and blind molecular docking studies of them to the COX-2 enzyme were undertaken to obtain binding affinities for judging whether the compounds could act as anti-inflammatory agents. The compounds interact with the key residues: Arg120, Val349, Leu352, Tyr355, Val523, Ala527, Ser530, and Leu531 of the active enzyme pocket. Molecular dynamics studies predicted that the complexes of 4a and 4b with COX-2 are structurally stable and no major conformational changes were observed. Confirmation of the docking and simulation data was achieved by a binding free energies analysis that indicated the dominance of van der Waals energy. The compounds are drug-like molecules as they obey all prominent drug-like rules and have acceptable pharmacokinetic profiles. To investigate the relationship between their intrinsic electronic properties and their possible similarities to actual drugs, the gas-phase DFT optimizations and NBO analyses were also performed in this study.
Learn More >Rheumatoid arthritis (RA) is an inflammatory type of arthritis that causes joint pain and damage. The inflammatory cell infiltration (e.g., M1 macrophages), the poor O supply at the joint, and the excess reactive oxygen species (ROS)-induced oxidative injury are the main causes of RA. We herein report a polydopamine (PDA)-coated CeO-dopped zeolitic imidazolate framework-8 (ZIF-8) nanocomposite CeO-ZIF-8@PDA (denoted as ) that can synergistically treat RA. Under near-infrared (NIR) light irradiation, PDA efficiently scavenges ROS and results in an increased temperature in the inflamed area because of its good light-to-heat conversion efficiency. The rise of temperature serves to obliterate hyper-proliferative inflammatory cells accumulated in the diseased area while vastly promoting the collapse of the acidic-responsive skeleton of ZIF-8 to release the encapsulated CeO. The released CeO exerts its catalase-like activity to relieve hypoxia by generating oxygen via the decomposition of HO highly expressed in the inflammatory sites. Thus, the constructed composite can treat RA through NIR-photothermal/ROS-scavenging/oxygen-enriched combinative therapy and show good regression of pro-inflammatory cytokines and hypoxia-inducible factor-1α (HIF-1α) in vitro and promising therapeutic effect on RA in rat models. The multimodal nano-platform reported herein is expected to shed light on the design of synergistic therapeutic nanomedicine for effective RA therapy.
Learn More >Headache is one of the most frequently reported symptoms in post-COVID patients. The clinical phenotype of COVID-19 headache combines phenotypic features of both tension-type headache (TTH) and migraine. We aimed to assess the effectiveness, side effects and predictors of amitriptyline (AMT) response in a real-world study setting.
Learn More >Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Learn More >Chemokine-opioid crosstalk is a physiological crossroads for influencing therapeutic and adverse effects of opioids. Activation of chemokine receptors, especially CCR2, CCR5 and CXCR4, reduces opioid-induced analgesia by desensitizing OPRM1 receptors. Chemokine receptor antagonists (CRAs) enhance opioid analgesia, but knowledge about how CRAs impact adverse opioid effects remains limited. We examined effects of RAP-103, a multi-CRA orally active peptide analog of "DAPTA", on opioid-derived dependence, reinforcement, and respiratory depression in male rats and on changes in chemokine and OPRM1 (µ opioid) receptor levels in mesolimbic substrates during opioid abstinence. In rats exposed to chronic morphine (75 mg pellet x 7 d), daily RAP-103 (1 mg/kg, IP) treatment reduced the severity of naloxone-precipitated withdrawal responses. For self-administration (SA) studies, RAP-103 (1 mg/kg, IP) reduced heroin acquisition (0.1 mg/kg/inf) and reinforcing efficacy (assessed by motivation on a progressive-ratio reinforcement schedule) but did not impact sucrose intake. RAP-103 (1-3 mg/kg, IP) also normalized the deficits in oxygen saturation and enhancement of respiratory rate caused by morphine (5 mg/kg, SC) exposure. Abstinence from chronic morphine elicited brain-region specific changes in chemokine receptor protein levels. CCR2 and CXCR4 were increased in the ventral tegmental area (VTA), whereas CCR2 and CCR5 were reduced in the nucleus accumbens (NAC). Effects of RAP-103 (1 mg/kg, IP) were focused in the NAC, where it normalized morphine-induced deficits in CCR2 and CCR5. These results identify CRAs as potential biphasic function opioid signaling modulators to enhance opioid analgesia and inhibit opioid-derived dependence and respiratory depression.
Learn More >Intervertebral disc (IVD) degeneration is accompanied by mechanical and gene expression changes to IVDs. SPARC-null mice display accelerated IVD degeneration, and treatment with (toll-like receptor 4 (TLR4) inhibitor) TAK-242 decreases proinflammatory cytokines and pain. This study examined if chronic TAK-242 treatment impacts mechanical properties and gene expression associated with IVD degeneration in SPARC-null mice.
Learn More >Chronic post-surgical pain predictive scores exist, but none has yet demonstrated an impact on patient care. Van Driel and colleagues offer an additional perspective on early postoperative detection of patient at risk of chronic post-surgical pain to enable early interventions in prevention and treatment. The authors derived and validated a model based on four easily obtainable predictors that could help clinicians assess and treat patients at risk. Additional work is needed to prove reliability and clinical benefit of chronic post-surgical pain prediction and intervention.
Learn More >There has been a growing interest in the use of complementary and alternative medicine in modern pain management strategies on behalf of both patients and clinicians. Nonpharmacologic modalities such as cryotherapy, acupuncture, music, and mind-body therapies have been shown to aid in symptom control and improve quality of life in patients suffering from acute and chronic pain, and there is a growing body of literature demonstrating their feasibility, acceptability, and efficacy in the perioperative period. Here, we provide a brief review of the current evidence supporting the use of complementary therapies within existing perioperative pain management strategies and highlight evidence-based protocols to facilitate implementation into modern surgical practice.
Learn More >Pain and pain management in the elderly population is a significant social and medical problem. Pain sensation is a complex phenomenon that typically involves activation of peripheral pain-sensing neurons (nociceptors) which send signals to the spinal cord and brain that are interpreted as pain, an unpleasant sensory experience. In this work, young (4-5 months) and aged (26-27 months) Fischer 344 x Brown Norway (F344xBN) rats were examined for nociceptor sensitivity to activation by thermal (cold and heat) and mechanical stimulation following treatment with inflammatory mediators and activators of transient receptor potential (TRP) channels. Unlike other senses that decrease in sensitivity with age, sensitivity of hindpaw nociceptors to thermal and mechanical stimulation was not different between young and aged F344xBN rats. Intraplantar injection of bradykinin (BK) produced greater thermal and mechanical allodynia in aged versus young rats, whereas only mechanical allodynia was greater in aged rats following injection of prostaglandin E (PGE). Intraplantar injection of TRP channel activators, capsaicin (TRPV1), mustard oil (TRPA1) and menthol (TRPM8) each resulted in greater mechanical allodynia in aged versus young rats and capsaicin-induced heat allodynia was also greater in aged rats. A treatment-induced allodynia that was greater in young rats was never observed. The anti-allodynic effects of intraplantar injection of kappa and delta opioid receptor agonists, salvinorin-A and D-Pen,D-Pen]enkephalin (DPDPE), respectively, were greater in aged than young rats, whereas mu opioid receptor agonists, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and morphine, were not effective in aged rats. Consistent with these observations, in primary cultures of peripheral sensory neurons, inhibition of cAMP signaling in response to delta and kappa receptor agonists was greater in cultures derived from aged rats. By contrast, mu receptor agonists did not inhibit cAMP signaling in aged rats. Thus, age-related changes in nociceptors generally favor increased pain signaling in aged versus young rats, suggesting that changes in nociceptor sensitivity may play a role in the increased incidence of pain in the elderly population. These results also suggest that development of peripherally-restricted kappa or delta opioid receptor agonists may provide safer and effective pain relief for the elderly.
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