生物谷報(bào)道：研究人員在12月號(hào)的《自然—神經(jīng)科學(xué)》上報(bào)告說(shuō)，一種自然產(chǎn)生的疼痛緩釋劑可能會(huì)加劇而不是緩解另一種特殊的生理疼痛,。作者在論文中指出,，內(nèi)源性鴉片是一種激活鴉片或嗎啡受體的小蛋白質(zhì)，但它通過(guò)激活不同類型的受體而產(chǎn)生這種效果,。
強(qiáng)啡肽是一種內(nèi)源性鴉片,，通常情況下它在鴉片受體內(nèi)發(fā)揮抑制慢性疼痛的作用。Josephine Lai和同事對(duì)強(qiáng)啡肽進(jìn)行了研究,。在類似于神經(jīng)損傷的部分慢性疼痛癥患者體內(nèi)有高水平的強(qiáng)啡肽,，但與其他內(nèi)源性鴉片不同的是，強(qiáng)啡肽實(shí)際上會(huì)加劇疼痛,。作者解釋了這種令人困擾的現(xiàn)象：強(qiáng)啡肽也能激活脊髓中緩激肽受體,，這種受體能導(dǎo)致對(duì)疼痛的超敏感性。一種能抑制緩激肽受體的藥物能抵御神經(jīng)性的疼痛,，但它只能在強(qiáng)啡肽水平提高時(shí)才會(huì)這種發(fā)揮作用,。在強(qiáng)啡肽的作用下,，缺失強(qiáng)啡肽受體的小鼠沒(méi)有表現(xiàn)出疼痛的加劇。
這些新發(fā)現(xiàn)指出,，在將新的鴉片藥物應(yīng)用于疼痛治療前,，應(yīng)仔細(xì)評(píng)估它們對(duì)緩激肽受體和鴉片受體的作用。新發(fā)現(xiàn)也許有助于開(kāi)發(fā)一種全新的治療慢性疼痛的藥物,。
Figure 1. Dynorphin A2–13 (dynA2–13) induces calcium influx in DRG and F-11 cells.
A representative recording of the change in ratio of 340 to 380 nm fura-2 fluorescence over time from embryonic DRG (a) and F-11 (b) cells in response to dynorphin A2–13 and KCl given at 60 s interval. (c) A representative recording of the change in ratio of 340 to 380 nm fura-2 fluorescence over time from a cell without calcium in the bath solution. (d) Cumulative score of dynorphin A2–13-responsive cells as a percentage of total number of cells recorded. n = 663 ([Ca2+]o), 198 ([Ca2+]o-free), and 170 (CdCl2, NiCl2). (e) Dynorphin A2–13 did not significantly stimulate PI hydrolysis in F-11 cells up to 10 M. Data are expressed as the mean s.e.m. from 3 independent experiments. Bradykinin was used as the positive control.
原文出處：
Nature Neuroscience December 2006, Volume 9 No 12
Dynorphin A activates bradykinin receptors to maintain neuropathic pain pp1534 - 1540
Josephine Lai, Miaw-Chyi Luo, Qingmin Chen, Shouwu Ma, Luis R Gardell, Michael H Ossipov & Frank Porreca
Published online: 19 November 2006 | doi:10.1038/nn1804
Abstract | Full text | PDF (243K) | Supplementary Information
See also: News and Views by Altier & Zamponi
相關(guān)基因：
BDKRB1
Official Symbol: BDKRB1 and Name: bradykinin receptor B1 [Homo sapiens]
Other Aliases: B1BKR, B1R, BKB1R, BKR1, BRADYB1
Other Designations: BK-1 receptor; bradykinin B1 receptor; bradykinin receptor 1
Chromosome: 14; Location: 14q32.1-q32.2
MIM: 600337
GeneID: 623
BDKRB2
Official Symbol: BDKRB2 and Name: bradykinin receptor B2 [Homo sapiens]
Other Aliases: B2R, BK-2, BK2, BKR2, BRB2, DKFZp686O088
Chromosome: 14; Location: 14q32.1-q32.2
MIM: 113503
GeneID: 624
作者簡(jiǎn)介：
Josephine Lai
Professor of Pharmacology and Molecular & Cellular Biology
Ph.D., Imperial College, University of London, 1985
Pharmacology of neuropathic pain, using nerve ligation injury in the rat as a model.
Research Interests
Spinal Dynorphin and Neuropathic Pain
Dynorphin is a neuropeptide that has unusual properties. It is structurally and pharmacologically defined as an endogenous opioid peptide that inhibits neuronal activity, yet at higher doses it is excitotoxic and induces long lasting abnormal pain. We have extensively characterized the neuronal excitatory actions of dynorphin by pharmacological, physiological and anatomical approaches, and are leaders in the elucidation of the mechanisms of action of dynorphin in chronic pain. The significance of these studies hopefully will pave the way to new therapeutics for the treatment of chronic pain based on dynorphin and its receptors as therapeutic targets.
Sodium Channels and Neuropathic Pain
Sodium channel activity is fundamental to the function of all neurons. Abnormal activity of these channels is critical to the development of chronic pain upon nerve injury. The utility of sodium channel blockers in chronic pain management is limited by severe side effects. We have established compelling evidence that one of the sodium channel sub-types, NaV1.8, is a potential therapeutic target as a selective blockade of this channel is sufficient to block abnormal pain. Because its expression is restricted to peripheral sensory neurons, drugs that are selective blockers for this channel should be effective with no central side effects.
select Publications
Any link on the below references will take you off of the BMCB site and to an abstract of that particular paper.
Agnes. R.S., Y.S. Lee, P. Davis, S.W. Ma, H. Badghis, F. Porreca, J. Lai, and V.J. Hruby. 2006. Structure-activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. Journal of Medicinal Chemistry 49: 2868-2875.
Gardell, L.R., t. King, M.H. Ossipov, K.C. Rice, J. Lai, T.W. Vanderah, and F. Porreca. 2006. Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neuroscience Letters 396: 44-49.
Dogrul, A., E.J. Bilsky, M.H. Ossipov, J. Lai, and F. Porreca. 2005. Spinal L-type calcium channel blockade abolishes opioid-induced sensory hypersensitivity and antinociceptive tolerance. Anesthesia and Analgesia 101: 1730-1735.
King, T., M.H. Ossipov, T.W. Vanderah, F. Porreca, and J. Lai. 2005. Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals 14: 194-205.
Luo, M.C., D.Q. Zhang, S.W. Ma, Y.Y. Huang, S.J. Shuster, F. Porreca, and J. Lai. 2005. An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons. Molecular Pain 1: 29.
King, T., L.R. Gardell, R. Wang, A. Vardanyan, M.H. Ossipov, T.P. Malan Jr, T.W. Vanderah, S.P. Hunt, V.J. Hruby, J. Lai, and F. Porreca. 2005. Role of NK-1 neurotransmission in opioid-induced hyperalgesia. Pain 116: 276-288.
Ossipov, M.H., J. Lai, T. King, T.W. Vanderah, and F. Porreca. 2005. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 80: 319-324.
Xie, J.Y., D.S. Herman, C.O. Stiller, L.R. Gardell, M.H. Ossipov, J. Lai, F. Porreca, and T.W. Vanderah. 2005. Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. Journal of Neuroscience 25: 409-416.
Ossipov, M.H., J. Lai, T. King, T.W. Vanderah, T.P. Malan Jr, V.J. Hruby, and F. Porreca. 2004. Antinociceptive and nociceptive actions of opioids. Journal of Neurobiology 61: 126-148.
Chen, Q., T. King, T.W. Vanderah, M.H. Ossipov, T.P. Malan Jr, J. Lai, and F. Porreca. 2004. Differential blockade of nerve injury-induced thermal and tactile hypersensitivity by systemically administered brain-penetrating and peripherally restricted local anesthetics. The Journal of Pain 5: 281-289.
Vanderah, T.W., C.D. Schteingart, J. Trojnar, J.L. Junien, J. Lai, and P.J. Riviere. 2004. FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): A peripheral efficacious kappa opioid agonist with unprecedented selectivity. The Journal of Pharmacology and Experimental Therapeutics 310: 326-333.
Lai J, Porreca F, Hunter JC, Gold MS. 2004. Voltage-gated sodium channels and hyperalgesia. Annual Review of Pharmacology and Toxicology 44: 371-397
