Yashpal K, Pitcher G M, Parent A, Quirion R, Coderre T J
Clinical Research Institute of Montreal, Department of Psychiatry, McGill University, Canada.
J Neurosci. 1995 May;15(5 Pt 1):3263-72. doi: 10.1523/JNEUROSCI.15-05-03263.1995.
We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the formalin test. This study compared the effects of pharmacological inhibition of PKC with either GF 109203X or chelerythrine on persistent pain following noxious chemical stimulation with its effects on mechanical hyperalgesia, which develops in the hindpaw contralateral to an injury produced by noxious thermal stimulation. Furthermore, we have assessed changes in membrane-associated PKC in spinal cord in response to both noxious chemical and thermal stimulation. Nociceptive responses, to a hindpaw injection of 50 microliters of 2.5% formalin, and flexion reflex thresholds, to mechanical stimulation (Randall-Selitto test) in the hindpaw contralateral to a thermal injury (15 sec immersion in water at 55 degrees C), were assessed following intrathecal injection of PKC inhibitors (GF 109203X or chelerythrine). Changes in the levels of membrane-associated PKC, as assayed by quantitative autoradiography of the specific binding of 3H-phorbol-12,13-dibutyrate (3H-PDBu) in spinal cord sections, were assessed in rats after noxious chemical (50 microliters of 5.0% formalin) and noxious thermal (90 sec immersion in water at 55 degrees C) stimulation. Inhibitors of PKC (GF 109203X, chelerythrine), produced significant reductions of nociceptive responses to 2.5% formalin, as well as a significant reduction in the mechanical hyperalgesia in the hindpaw contralateral to a thermal injury. In addition, both noxious chemical and thermal stimulation produced significant increases in specific 3H-PDBu binding in the dorsal horn of the lumbar spinal cord, likely reflecting alterations in membrane-associated PKC. The results provide both pharmacological and anatomical evidence that persistent pain produced by chemical stimulation with formalin and mechanical hyperalgesia in the hindpaw contralateral to a thermal injury are influenced by the translocation and activation of PKC in spinal cord dorsal horn neurons.
我们之前曾提出蛋白激酶C（PKC）在福尔马林试验中导致持续性疼痛。本研究比较了用GF 109203X或白屈菜红碱对PKC进行药理学抑制对有害化学刺激后持续性疼痛的影响及其对机械性痛觉过敏的影响，机械性痛觉过敏在与有害热刺激所致损伤对侧的后爪出现。此外，我们评估了脊髓中膜相关PKC在有害化学和热刺激后的变化。在鞘内注射PKC抑制剂（GF 109203X或白屈菜红碱）后，评估后爪注射50微升2.5%福尔马林后的伤害性反应以及热损伤（在55℃水中浸泡15秒）对侧后爪机械刺激（兰德尔-塞利托试验）的屈曲反射阈值。通过对脊髓切片中3H-佛波醇-12,13-二丁酸酯（3H-PDBu）特异性结合进行定量放射自显影测定膜相关PKC水平的变化，在大鼠接受有害化学刺激（50微升5.0%福尔马林）和有害热刺激（在55℃水中浸泡90秒）后进行评估。PKC抑制剂（GF 109203X、白屈菜红碱）显著降低了对2.5%福尔马林的伤害性反应，以及热损伤对侧后爪的机械性痛觉过敏。此外，有害化学和热刺激均使腰脊髓背角的特异性3H-PDBu结合显著增加，这可能反映了膜相关PKC的改变。结果提供了药理学和解剖学证据，表明福尔马林化学刺激产生的持续性疼痛以及热损伤对侧后爪的机械性痛觉过敏受脊髓背角神经元中PKC易位和激活的影响。
