Nature：无副作用的新型止痛药
慢性疼痛长年累月地折磨着很多人，有效的治疗药物并不多，且通常会产生呆静（sedation）、上瘾及耐药性等副作用。一个国际科学家小组近日发现一种药物能很好地治疗鼠类的慢性疼痛，并且不会带来上述副作用。该药对人体是否同样起作用还有待证实，但研究人员对于在人体中找到该药标靶持谨慎乐观态度。相关论文发表在1月17日的《自然》（Nature）杂志上。
这种药物属于苯(并)二氮卓类（benzodiazepines），苯(并)二氮卓类药物广泛用于镇静和治疗忧虑，它作用于大脑中与痛觉有关的路径，但并不能非常有效地缓解疼痛。
瑞士苏黎世大学的Hanns Ulrich Zeilhofer领导小组对其中的原因进行了研究。研究人员首先将药物“安定”（diazepam）注射进小鼠的脊椎中，结果发现，小鼠正在经受的注射疼痛和因神经挤压带来的疼痛（类似于慢性疼痛）均得到了缓解。
安定作用的受体为GABA（γ-aminobutyric acid），它具有不同的亚组（subunits），具有的功能可能也各不相同。研究人员利用四种不同类型的突变小鼠（每种类型小鼠的GABA受体都有一种不同的亚组失活），对安定的作用机制进行了研究。
结果发现，其中的两种亚组——α2和α3，对于安定缓解疼痛是必需的。另外一种亚组——α1，则会使人产生昏睡的感觉。Zeilhofer表示，我们所展现的就是哪种受体应该作为标靶。
研究人员接下来又试验了另一种苯(并)二氮卓类化合物——L-838,417的作用，L-838,417已知不会作用于致人昏睡的GABA受体α1亚组。他们让大鼠口服这种化合物，结果成功地缓解了大鼠的疼痛且不会产生呆静作用。而且，在持续的一段治疗时间里，它能一直起作用。
功能核磁共振成像（fMRI）结果显示，该化合物降低了大鼠大脑中一些区域的活性，这些区域与疼痛以及由疼痛带来的忧伤情绪有关。
研究人员表示，下一步就是寻找能够在人体中起相同作用的药物。美国麻省综合医院的麻醉学家Clifford Woolf 对这一目标持谨慎乐观态度，他说：“前临床研究和在人体中进行概念验证之间总是有很长的路要走。”
生物谷推荐原始出处：
Nature 451, 330-334 (17 January 2008) | doi:10.1038/nature06493; Received 11 October 2007; Accepted 19 November 2007
Reversal of pathological pain through specific spinal GABAA receptor subtypes
Julia Knabl1, Robert Witschi2, Katharina Hösl1, Heiko Reinold1, Ulrike B. Zeilhofer1, Seifollah Ahmadi1,6, Johannes Brockhaus2,6, Marina Sergejeva1, Andreas Hess1, Kay Brune1, Jean-Marc Fritschy2, Uwe Rudolph2,4, Hanns Möhler2,3,5 & Hanns Ulrich Zeilhofer1,2,3
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany
- Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland
- Institute of Pharmaceutical Sciences, ETH Zurich, CH-8093 Zurich, Switzerland
- Laboratory of Genetic Neuropharmacology, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts 02478, USA
- Collegium Helveticum, CH-8092 Zurich, Switzerland
- Present addresses: Department of Physiology, University of Bonn, D-53111 Bonn, Germany (S.A.); Department of Physiology, University of Münster, D-48149 Münster, Germany (J.B.).
Correspondence to: Hanns Ulrich Zeilhofer1,2,3 Correspondence and requests for materials should be addressed to H.U.Z. (Email: zeilhofer@pharma.uzh.ch).
Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment1, 2. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology3, 4, 5, 6, 7. Facilitation of spinal 
-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABAA receptors should be able to compensate for this loss8, 9. With the use of GABAA-receptor point-mutated knock-in mice in which specific GABAA receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands10, 11, 12, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABAA receptors containing the 
2 and/or 3 subunits. We show that their selective activation by the non-sedative ('1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.
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