Dogrul Ahmet, Gardell Luis R, Ma Shouwu, Ossipov Michael H, Porreca Frank, Lai Josephine
Department of Pharmacology, School of Medicine, Gülhane Military Medical Academy, 06018, Etlik, Ankara, Turkey.
Pain. 2002 Nov;100(1-2):203-9. doi: 10.1016/s0304-3959(02)00302-0.
Recent studies demonstrate the possible existence of tonic modulatory control of nociceptive input mediated by spinal cannabinoid receptors (CB1). Accordingly, it is predicted that a reduction in the spinal CB1 receptors may enhance sensitivity to sensory stimuli and a decrease in spinal antinociceptive potency to cannabinoid agonists. An antisense oligodeoxynucleotide (ODN) specific to the CB1 receptor was used to 'knock-down' CB1 receptors in the lumbar spinal cord and dorsal root ganglia by the local, repeated intrathecal (i.th.) administration of the ODN. This treatment resulted in a decrease in lumbar spinal CB1 receptor expression accompanied by a decrease in the response thresholds to both innocuous tactile and noxious thermal stimuli. The antinociceptive action of the CB1 agonist, WIN 55,212-2, by i.th. administration was also significantly attenuated after treatment with the antisense ODN. Similar treatment using a mismatch control ODN had no effect on receptor protein or on sensory thresholds. The effects of the antisense ODN treatment on sensory thresholds were fully reversed after discontinuation of the ODN injection. The antisense ODN treated rats also showed a significant increase in lumbar spinal dynorphin A. Acute i.th. injection of MK-801 or an antidynorphin antiserum blocked the antisense ODN-induced tactile and thermal hypersensitivity. These data support the possibility of endogenous inhibitory cannabinoid tone to limit spinal afferent input of thermal and tactile stimuli. Lifting of this inhibitory tone through a 'knock-down' of spinal CB1 receptors apparently lowers the thresholds for sensory input, as reflected by the actions of MK-801 to block tactile and thermal hypersensitivity. The increased spinal dynorphin may act to further promote afferent outflow and abnormal pain because sequestration of spinal dynorphin with antiserum also reverses the manifestations of abnormal pain following knock-down of CB1 receptors.
近期研究表明，脊髓大麻素受体（CB1）介导的伤害性传入可能存在紧张性调节控制。因此，预计脊髓CB1受体减少可能会增强对感觉刺激的敏感性，并降低脊髓对大麻素激动剂的抗伤害效能。一种针对CB1受体的反义寡脱氧核苷酸（ODN）通过局部、反复鞘内注射该ODN，用于“敲低”腰段脊髓和背根神经节中的CB1受体。这种处理导致腰段脊髓CB1受体表达减少，同时对无害触觉和有害热刺激的反应阈值降低。鞘内注射CB1激动剂WIN 55,212-2的抗伤害作用在用反义ODN处理后也显著减弱。使用错配对照ODN进行类似处理对受体蛋白或感觉阈值没有影响。停止注射ODN后，反义ODN处理对感觉阈值的影响完全逆转。反义ODN处理的大鼠腰段脊髓强啡肽A也显著增加。急性鞘内注射MK-801或抗强啡肽抗血清可阻断反义ODN诱导的触觉和热超敏反应。这些数据支持内源性抑制性大麻素张力限制热和触觉刺激脊髓传入输入的可能性。通过“敲低”脊髓CB1受体解除这种抑制性张力显然会降低感觉输入的阈值，如MK-801阻断触觉和热超敏反应的作用所示。脊髓强啡肽增加可能会进一步促进传入神经流出和异常疼痛，因为用抗血清隔离脊髓强啡肽也会逆转CB1受体敲低后异常疼痛的表现。
