Structural features of mammalian histidine decarboxylase reveal the basis for specific inhibition

Gout and pain are synonymous, and a study in this issue of the BJP reports a novel anti-nociceptive effect of allopurinol, the drug most commonly used to treat gout. Allopurinol works by inhibiting xanthine oxidase (XO), the enzyme responsible for converting hypoxanthine to uric acid which is deposited as crystals in the joints of gout sufferers. Hypoxanthine is a metabolite of, and a possible precursor to, adenosine. Schmidt et al., find that acute inhibition of XO with allopurinol produces a modest adenosine A₁ receptor-mediated anti-nociceptive effect in common tests of chemical and thermal nociception in mice. A concomitant increase in cerebrospinal fluid levels of adenosine supports their hypothesis that inhibiting XO increases adenosine levels via salvage from hypoxanthine. Elevating endogenous adenosine levels by inhibiting metabolism is a well-established strategy for producing anti-nociception in many preclinical models, but inhibiting XO is likely to be particularly beneficial in some chronic pain states because of the pro-nociceptive reactive oxygen species that are produced by XO activity. Thus, allopurinol may have unexpected benefits in pain associated with chronic inflammation, diabetes and vascular dysfunction.     

不同产地北细辛和华细辛镇痛抗炎药效学评价

目的:进行不同产地的北细辛和华细辛镇痛抗炎药效学评价。方法:以醋酸扭体试验、热板试验对细辛进行镇痛作用评价;以二甲苯致鼠耳肿胀试验对细辛进行抗炎作用评价。结果:12个不同产地的北细辛和华细辛样品均有镇痛和抗炎作用,疼痛抑制率7个北细辛样品在27%～61%,5个华细辛样品在40%～59%。6个产地北细辛的炎症抑制率(50%～70%)强于5个产地的华细辛炎症抑制率(34%～48%)。不同产地同一品种的细辛镇痛抗炎作用差异显著。北细辛:醋酸扭体实验结果显示4个吉林产细辛镇痛作用(38%～57%)均强于黑龙江产细辛(34%);热板实验结果显示黑龙江产细辛镇痛作用(43%)强于2个辽宁产细辛(29%～36%)。华细辛:醋酸扭体实验显示3个陕西产细辛镇痛作用(47%～49%)均强于湖北产细辛(40%);热板实验显示3个陕西产细辛镇痛作用(45%～59%)强于重庆产细辛(40%)。鼠耳肿胀实验结果显示北细辛4个吉林产细辛抗炎作用(51%～63%)均优于黑龙江产细辛(50%)。道地性分析表明,北细辛及华细辛道地药材的镇痛作用有强于各自非道地药材的趋势;北细辛道地药材的抗炎作用较非道地药材强,但华细辛道地药材和非道地药材在抗炎作用方面无明显差异。结论:不同产地的细辛均有镇痛抗炎作用,但作用强度明显不同,显示细辛具有一定程度的道地性。     

Inhibition of Nav1.7 channel by a novel blocker QLS-81 for alleviation of neuropathic pain

Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti-nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized. Here, we report the electrophysiological and pharmacodynamic characterization of QLS-81 as a Nav1.7 channel inhibitor with promising anti-nociceptive activity. In whole-cell recordings of HEK293 cells stably expressing Nav1.7, QLS-81 (IC₅₀ at 3.5 ± 1.5 μM) was ten-fold more potent than its parent compound ralfinamide (37.1 ± 2.9 μM) in inhibiting Nav1.7 current. QLS-81 inhibition on Nav1.7 current was use-dependent. Application of QLS-81 (10 μM) caused a hyperpolarizing shift of the fast and slow inactivation of Nav1.7 channel about 7.9 mV and 26.6 mV, respectively, and also slowed down the channel fast and slow inactivation recovery. In dissociated mouse DRG neurons, QLS-81 (10 μM) inhibited native Nav current and suppressed depolarizing current pulse-elicited neuronal firing. Administration of QLS-81 (2, 5, 10 mg· kg⁻¹· d⁻¹, i.p.) in mice for 10 days dose-dependently alleviated spinal nerve injury-induced neuropathic pain and formalin-induced inflammatory pain. In addition, QLS-81 (10 μM) did not significantly affect ECG in guinea pig heart ex vivo; and administration of QLS-81 (10, 20 mg/kg, i.p.) in mice had no significant effect on spontaneous locomotor activity. Taken together, our results demonstrate that QLS-81, as a novel Nav1.7 inhibitor, is efficacious on chronic pain in mice, and it may hold developmental potential for pain therapy.     

Suppression of complete Freund＇s adjuvant-induced adjuvant arthritis by cobratoxin

Aim： Cobratoxin （CTX）, the long-chain α-neurotoxin from Thailand cobra venom, has been demonstrated to have analgesic action in rodent pain models. The present study evaluated the anti-inflammatory and anti-nociceptive effects of CTX on adjuvant arthritis （AA） in rats. Methods： Arthritis was induced by injection of complete Freund＇s adjuvant （CFA） in rats. Paw swelling and hyperalgesia of AA rats were measured at various times after CFA administration. Tumor necrosis factor-a （TNF-α）, interleukin-1 （IL-1）, interleukin-2 （IL-2） and interleukin-10 （IL-10） levels in serum were determined with ELISA. Histopathological changes in synoviocytes were examined under a microscope. Involvement of the cholinergic system in the effects of CTX was examined by pretreatment of animals with the α7 nicotinic receptor （α7-nAChR） antagonist methyllycaconitine （MLA）. Results： CFA induced marked paw swelling and reduced thresholds of mechanical and cold-induced paw withdrawal. The levels of TNF-α, IL-1 and IL-2 in the serum of AA rats were increased, whereas the level of IL-10 was decreased. Histopathological examination of synoviocytes showed pronounced inflammation and accumulation of collagen. The administration of CTX （17.0 μg/kg, ip） significantly reduced paw swelling and mechanical and thermal hyperalgesia. CTX also reduced the production ofTNF-α, IL-1, and IL-2 but increased the production of IL-10 and altered pathohistological changes. The analgesic and anti-inflammatory efficacy of CTX was significantly reduced by MLA （3 mg/kg, sc）. Conclusion： These results indicate that CTX has a beneficial effect on CFA-induced arthritis by modulating the production of inflammatory cytokines, α7-nAChR appears to mediate the anti-nociceptive and anti-inflammatory actions of CTX.