Research progress on targets for analgesics / 中国药理学通报

Pain as a clinical common symptom is one of the most serious problems to threaten human health,therefore,pain management is one of the main aspects of clinical medication.This review briefly described the existing and the novel analgesic targets,in order to study and develop new kinds of analgesic drugs with high efficacy,less side effects and no resistance and addiction,which aims to provide a reference for the clinical application.

Etifoxine for Pain Patients with Anxiety

Etifoxine (etafenoxine, Stresam(R)) is a non-benzodiazepine anxiolytic with an anticonvulsant effect. It was developed in the 1960s for anxiety disorders and is currently being studied for its ability to promote peripheral nerve healing and to treat chemotherapy-induced pain. In addition to being mediated by GABA(A)alpha2 receptors like benzodiazepines, etifoxine appears to produce anxiolytic effects directly by binding to beta2 or beta3 subunits of the GABA(A) receptor complex. It also modulates GABA(A) receptors indirectly via stimulation of neurosteroid production after etifoxine binds to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane in the central and peripheral nervous systems, previously known as the peripheral benzodiazepine receptor (PBR). Therefore, the effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine is used for various emotional and bodily reactions followed by anxiety. It is contraindicated in situations such as shock, severely impaired liver or kidney function, and severe respiratory failure. The average dosage is 150 mg per day for no more than 12 weeks. The most common adverse effect is drowsiness at the initial stage. It does not usually cause any withdrawal syndromes. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. It potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of TSPO. It seems promising that non-benzodiazepine anxiolytics including etifoxine will replenish shortcomings of benzodiazepines and selective serotonin reuptake inhibitors according to animated studies related to TSPO.

Differential Role of Central GABA Receptors in Nociception of Orofacial Area in Rats

The present study investigated the role of central GABA(A) and GABA(B) receptors in orofacial pain in rats. Experiments were conducted on Sprague-Dawley rats weighing between 230 and 280 g. Intracisternal catheterization was performed for intracisternal injection, under ketamine anesthesia. Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia and inferior alveolar nerve injury-induced mechanical allodynia were employed as orofacial pain models. Intracisternal administration of bicuculline, a GABA(A) receptor antagonist, produced mechanical allodynia in naive rats, but not thermal hyperalgesia. However, CGP35348, a GABA(B) receptor antagonist, did not show any pain behavior in naive rats. Intracisternal administration of muscimol, a GABA(A) receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. On the contrary, intracisternal administration of bicuculline also attenuated the mechanical allodynia in rats with inferior alveolar nerve injury. Intracisternal administration of baclofen, a GABA(B) receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. In contrast to GABA(A) receptor antagonist, intracisternal administration of CGP35348 did not affect either the thermal hyperalgesia or mechanical allodynia. Our current findings suggest that the GABA(A) receptor, but not the GABA(B) receptor, participates in pain processing under normal conditions. Intracisternal administration of GABA(A) receptor antagonist, but not GABA(B) receptor antagonist, produces paradoxical antinociception under pain conditions. These results suggest that central GABA has differential roles in the processing of orofacial pain, and the blockade of GABA(A) receptor provides new therapeutic targets for the treatment of chronic pain.

Changes of the amino acid receptors in solitary tract nucleus of rats with spinal cord injury / 第二军医大学学报

Objective: To investigate the changes of the amino acid receptors in solitary tract nucleus(NTS)of rats after spinal cord injury (SCI). Methods: The rat model of T4 spinal cord transection was used in this study. The study was divided into SCI group(n=5)and Control group(n=5). Changes in mean arterial pressure (MAP) and heart rate (HR) were observed at 1,2,3,4, and 6 weeks after SCI; and the protein expression of the glutamate N-methyl-D-aspartate receptor 1 (NMDA-R1) and gamma-aminobutyric acid receptor A α1 (GABAA-α1) in the NTS were detected by Western blotting analysis at different time points. Results: The MAP level was significantly decreased at 1-3 weeks after SCI (P<0.05), and it gradually recovered 4 weeks after SCI; the HR was significantly increased 1-4 weeks after SCI (P<0.05) and recovered at the 6th week. The results of Western blotting analysis showed that the protein expression of GABAA-α1 was significantly increased 2 weeks after SCI and significantly reduced at 4 and 6 weeks after SCI (P<0.05). Moreover, the ratio of NMDA-R1 to GABAA-α1 expression in NTS was significantly elevated after SCI(P<0.05). Conclusion: The adaptable changes of important receptors in the NTS following SCI may improve SCI-induced cardiovascular dysfunction.

Quantitative Autoradiographic Study on Receptor Regulation in the Basal Ganglia in Rat Model of Levodopa-induced Motor Complications / 华中科技大学学报（医学）（英德文版）

In order to study neurotransmitter receptor regulation in the basal ganglia involved in the functional changes underlying levodopa-induced motor complications,quantitative autoradiography was used to observe receptor bindings of dopamine D1 and D2,N-methyl-D-aspartate (NMDA),amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) and amino butyric acid (GABA) in the basal ganglia of rats that had unilateral nigrostriatal lesions and had been chronically treated with levodopa until motor complications developed.The rats were randomly assigned to three groups:normal,denervated and treatment-complicated groups.The results showed that response duration to levodopa became progressively shorter and abnormal involuntary movement (AIM) score was progressively increased during the course of levodopa treatment.Chronic treatment augmented DI receptors more than denervation,and reduced D2 receptors that were also increased by dopamine denervation.Striatal NMDA receptors were substantially up-regulated in the treatment-complicated group.Levodopa treatment did not change receptors of nigral AMPA,pailidai GABA,and subthalamic GABA,which remained the same as that in denervation group.However,chronic treatment reversed the increase ofnigral GABA receptors caused by the lesion.It was concluded that a shortening of response duration and AIM mimicked levodopa-induced motor complications of Parkinson's patients.These data suggested that up-regulation of dopamine D1 and NMDA receptors in the striatum leads to an imbalance of stimulation through the striatal output pathways,which is associated with levodopa-induced motor complications.

The Effect of Treatment with Intrathecal Ginsenosides in a Rat Model of Postoperative Pain / 대한통증학회지

BACKGROUND: Ginseng has been used to manage various types of pain in folk medicine. This study characterized the effect of treatment with intrathecal ginsenosides, the active components of ginseng in a postoperative pain model. METHODS: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters. An incision was made in the plantar surface of the hindpaw. Withdrawal thresholds following the application of a von Frey filament to the wound site were measured. To determine the role of the opioid or GABA receptors following treatment with the ginsenosides, naloxone, bicuculline (a GABAA receptor antagonist), and saclofen (a GABAB receptor antagonist) were administered intrathecally 10 min before the delivery of the ginsenosides and the changes of the withdrawal thresholds after application of the von Frey filament were observed. RESULTS: Treatment with the intrathecal ginsenosides increased the withdrawal threshold in a dose dependent manner. Pre-treatment with intrathecal naloxone reversed the antinociceptive effect of the ginsenosides. However, pre-treatment with intrathecal bicuculline and saclofen failed to have an effect on the activity of the ginsenosides. CONCLUSIONS: These results suggest that ginsenosides are effective to alleviate the postoperative pain evoked by paw incision. The opioid receptor, but not GABA receptors, may be involved in the antinociceptive action of the ginsenosides at the spinal level.

GABAB Receptor Modulation on the Antinociception of Intrathecal Sildenafil in the Rat Formalin Test / 대한통증학회지

BACKGROUND: A phosphodiesterase 5 inhibitor, sildenafil, has been effective against nociception. Several lines of evidence have demonstrated the role of the GABAergic pathway in the modulation of nociception. The impact of the GABA receptors on sildenafil was studied using the formalin test at the spinal level. METHODS: Male SD rats were prepared for intrathecal catheterization. The formalin test was induced by subcutaneous injection of formalin solution. The change in the activity of sildenafil was examined after pretreatment with GABA receptor antagonists (GABAA receptor antagonist, bicuculline; GABAB receptor antagonist, saclofen). RESULTS: Intrathecal sildenafil dose-dependently attenuated the flinching observed during phase 1 and 2 in the formalin test. The antinociceptive effect of sildenafil was reversed by the GABAB receptor antagonist (saclofen) but not by the GABAA receptor antagonist (bicuculline) in both phases. CONCLUSIONS: Intrathecal sildenafil suppressed acute pain and the facilitated pain state. The antinociception of sildenafil is mediated via the GABAB receptor, but not the GABAA receptor, at the spinal level.

Effects of Extracellular Chloride Ions on the Catfish Retinal Neurons

The catfish (Ictalurus punctatus) retinal neurons were investigated by using the intracellular recording techniques to analyze the function of the chloride ions in the light responses and the ionic mechanisms of the depolarizing actions by GABA. Experiments were performed in the superfused retina-eyecup preparation. The retina was exposed by exicising the cornea, iris, and vitreous. A piece of absorbent tissue with a hole large enough to expose the retina was centered over the eyecup to serve as a wick to draw off the superfusate. Diffuse light stimuli were generated by light-emitting diode positioned above the eyecup. The recordings were made with the use of borosilicate glass micropipettes fashioned from' omega dot' capillary tubing filled with 2 M potassium acetate. Voltage recordings were obtained using an amplifier and amplified signals were recorded on a storage oscillocope, penwriter, and a data recorder. In the catfish retina, the dark membrane potentials were depolarized and the light evoked responses were enhanced in the chloride"-free medium on the catfish horizontal cells. The amplitude of the light evoked potentials were increased by chloride free Ringer's solution on the ON- and OFF-bipolar cells. But the dark membrane potentials were hyperpolarized on the ON-bipolar cell and depolarized on the OFF-bipolar cells in the chloride free medium. The chloride free Ringer's solution changed the light response from ON-sustained to OFF-sustained without any change in amplitude on the ON-sustained cell. The depolarizing actions by GABA on the horizontal cells were maintained in chloride-free environment. But GABA did not abolished the light evoked potentials of the horizontal cell and the ON-sustained cell under the chloride free environment. The results suggest that chloride ion has important roles on the signal transmission of the dark periods in the catfish retina and the depolarizing actions by GABA on the neurons in the catfish retina might be chloride dependent.