Accepted

Inflammatory pain is one of the most common symptoms of clinical pain that seriously affects patient quality of life, but it currently has limited therapeutic options. Proanthocyanidins, a group of polyphenols enriched in plants and foods, have been reported to exert anti-inflammatory pain-alleviating effects. However, the mechanism by which proanthocyanidins relieve inflammatory pain in the central nervous system is unclear. In the present study, we observed that intrathecal injection of proanthocyanidins inhibited mechanical and thermal pain sensitivity in mice with inflammatory pain induced by Complete Freund's Adjuvant (CFA) injection. Electrophysiological results further showed that proanthocyanidins inhibited the frequency of spontaneous excitatory postsynaptic currents without affecting the spontaneous inhibitory postsynaptic currents or the intrinsic properties of parabrachial nucleus-projecting neurons in the spinal cord. The effect of proanthocyanidins may be mediated by their inhibition of phosphorylated activation of the PI3K/Akt/mTOR pathway molecules in dorsal root ganglia neurons. In summary, intrathecal injection of procyanidin induces an obvious anti-inflammatory pain effect in mice by inhibiting peripheral excitatory inputs to spinal neurons that send nociceptive information to supraspinal areas.

5-Lipoxygenase (5-LO) is the key enzyme in the formation of pro-inflammatory leukotrienes (LT) which play an important role in a number of inflammatory diseases. Accordingly, 5-LO inhibitors are frequently used to study the role of 5-LO and LT in models of inflammation and cancer. Interestingly, the therapeutic efficacy of these inhibitors is highly variable. Here we show that the frequently used 5-LO inhibitors AA-861, BWA4C, C06, CJ-13,610 and the FDA approved compound zileuton as well as the pan-LO inhibitor nordihydroguaiaretic acid interfere with prostaglandin E (PGE) release into the supernatants of cytokine-stimulated (TNFα/IL-1β) HeLa cervix carcinoma, A549 lung cancer as well as HCA-7 colon carcinoma cells with similar potencies compared to their LT inhibitory activities (IC values ranging from 0.1-9.1 µM). In addition, AA-861, BWA4C, CJ-13,610 and zileuton concentration-dependently inhibited bacterial lipopolysaccharide triggered prostaglandin (PG) release into human whole blood. Western Blot analysis revealed that inhibition of expression of enzymes involved in PG synthesis was not part of the underlying mechanism. Also, liberation of arachidonic acid which is the substrate for PG synthesis as well as PGH and PGE formation were not impaired by the compounds. However, accumulation of intracellular PGE was found in the inhibitor treated HeLa cells suggesting inhibition of PG export as major mechanism. Further, experiments showed that the PG exporter ATP-binding cassette transporter multidrug resistance protein 4 (MRP-4) is targeted by the inhibitors and may be involved in the 5-LO inhibitor-mediated PGE inhibition. In conclusion, the pharmacological effects of a number of 5-LO inhibitors are compound-specific and involve the potent inhibition of PGE export. Results from experimental models on the role of 5-LO in inflammation and pain using 5-LO inhibitors may be misleading and their use as pharmacological tools in experimental models has to be revisited. In addition, 5-LO inhibitors may serve as new scaffolds for the development of potent prostaglandin export inhibitors.

Dexmedetomidine, a highly selective α2-adrenoceptor agonist, has sedative, anxiolytic, analgesic, sympatholytic, and opioid-sparing properties and induces a unique sedative response which shows an easy transition from sleep to wakefulness, thus allowing a patient to be cooperative and communicative when stimulated. Recent studies indicate several emerging clinical applications via different routes. We review recent data on dexmedetomidine studies, particularly exploring the varying routes of administration, experimental implications, clinical effects, and comparative advantages over other drugs. A search was conducted on the PubMed and Web of Science libraries for recent studies using different combinations of the words "dexmedetomidine", "route of administration", and pharmacological effect. The current routes, pharmacological effects, and application categories of dexmedetomidine are presented. It functions by stimulating pre- and post-synaptic α2-adrenoreceptors within the central nervous system, leading to hyperpolarization of noradrenergic neurons, induction of an inhibitory feedback loop, and reduction of norepinephrine secretion, causing a sympatholytic effect, in addition to its anti-inflammation, sleep induction, bowel recovery, and sore throat reduction effects. Compared with similar α2-adrenoceptor agonists, dexmedetomidine has both pharmacodynamics advantage of a significantly greater α2:α1-adrenoceptor affinity ratio and a pharmacokinetic advantage of having a significantly shorter elimination half-life. In its clinical application, dexmedetomidine has been reported to present a significant number of benefits including safe sedation for various surgical interventions, improvement of intraoperative and postoperative analgesia, sedation for compromised airways without respiratory depression, nephroprotection and stability of hypotensive hemodynamics, reduction of postoperative nausea and vomiting and postoperative shivering incidence, and decrease of intraoperative blood loss. Although the clinical application of dexmedetomidine is promising, it is still limited and further research is required to enhance understanding of its pharmacological properties, patient selection, dosage, and adverse effects.

Tramadol (TMDL) is an opioid analgesic widely administered for the management of moderate to severe pain. On the other hand, TMDL is commonly abused in many countries because of its availability and cheap cost. Renal injury is related to high dose or chronic administration of TMDL. No precise mechanism for TMDL-induced renal damage has been identified so far. The current study aimed to evaluate the potential role of oxidative stress and mitochondrial impairment in the pathogenesis of TMDL-induced renal injury. For this purpose, rats were treated with TMDL (40 and 80 ​mg/kg, i.p, 28 consecutive days). A significant increase in serum Cr and BUN was detected in TMDL groups. On the other hand, TMDL (80 ​mg/kg) caused a substantial increase in urine glucose, ALP, protein, and γ-GT levels. Moreover, urine Cr was significantly decreased in TMDL-treated rats (40 and 80 ​mg/kg). Renal histopathological alterations included inflammation, necrosis, and tubular degeneration in the kidney of TMDL-treated animals. Reactive oxygen species (ROS) formation, increased oxidized glutathione (GSSG), lipid peroxidation, and protein carbonylation was increased, whereas total antioxidant capacity and reduced glutathione levels were considerably decreased in TMDL groups. Significant mitochondrial impairment was also detected in the form of mitochondrial depolarization, adenosine-tri-phosphate (ATP) depletion, mitochondrial permeabilization, lipid peroxidation, and decreased mitochondrial dehydrogenase activity in the kidney of TMDL (80 ​mg/kg)-treated animals. These data suggest mitochondrial impairment and oxidative stress as mechanisms involved in the pathogenesis of TMDL-induced renal injury.