Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
Mol Pain. 2010 Dec 17;6:94. doi: 10.1186/1744-8069-6-94.
Ablation of TRPV1-expressing nociceptive fibers with the potent capsaicin analog resiniferatoxin (RTX) results in long lasting pain relief. RTX is particularly adaptable to focal application, and the induced chemical axonopathy leads to analgesia with a duration that is influenced by dose, route of administration, and the rate of fiber regeneration. TRPV1 is expressed in a subpopulation of unmyelinated C- and lightly myelinated Adelta fibers that detect changes in skin temperature at low and high rates of noxious heating, respectively. Here we investigate fiber-type specific behaviors, their time course of recovery and molecular correlates of axon damage and nociception using infrared laser stimuli following an RTX-induced peripheral axonopathy.
RTX was injected into rat hind paws (mid-plantar) to produce thermal hypoalgesia. An infrared diode laser was used to stimulate Adelta fibers in the paw with a small-diameter (1.6 mm), high-energy, 100 msec pulse, or C-fibers with a wide-diameter (5 mm), long-duration, low-energy pulse. We monitored behavioral responses to indicate loss and regeneration of fibers. At the site of injection, responses to C-fiber stimuli were significantly attenuated for two weeks after 5 or 50 ng RTX. Responses to Adelta stimuli were significantly attenuated for two weeks at the highest intensity stimulus, and for 5 weeks to a less intense Adelta stimulus. Stimulation on the toe, a site distal to the injection, showed significant attenuation of Adelta responses for 7- 8 weeks after 5 ng, or 9-10 weeks after 50 ng RTX. In contrast, responses to C-fiber stimuli exhibited basically normal responses at 5 weeks after RTX. During the period of fiber loss and recovery, molecular markers for nerve regeneration (ATF3 and galanin) are upregulated in the dorsal root ganglia (DRG) when behavior is maximally attenuated, but markers of nociceptive activity (c-Fos in spinal cord and MCP-1 in DRG), although induced immediately after RTX treatment, returned to normal.
Behavioral recovery following peripheral RTX treatment is linked to regeneration of TRPV1-expressing Adelta and C-fibers and sustained expression of molecular markers. Infrared laser stimulation is a potentially valuable tool for evaluating the behavioral role of Adelta fibers in pain and pain control.
用强效辣椒素类似物树脂毒素（RTX）消融 TRPV1 表达的伤害性纤维可导致长期疼痛缓解。RTX 特别适用于局灶应用，诱导的化学轴突变导致镇痛作用，其持续时间受剂量、给药途径和纤维再生速度的影响。TRPV1 表达在未髓鞘化 C 纤维和轻度髓鞘化 Adelta 纤维的亚群中，分别检测到皮肤温度的低和高速变化时的伤害性加热。在这里，我们使用红外激光刺激，研究了 RTX 诱导的外周轴突病变后纤维类型特异性行为、其恢复的时间过程以及轴突损伤和伤害感受的分子相关性。
RTX 被注射到大鼠后爪（中足底）以产生热痛觉减退。使用红外二极管激光，用小直径（1.6 毫米）、高能、100 毫秒脉冲刺激爪中的 Adelta 纤维，或用大直径（5 毫米）、长持续时间、低能量脉冲刺激 C 纤维。我们监测行为反应以表明纤维的丧失和再生。在注射部位，用 5 或 50ng RTX 处理后两周，C 纤维刺激的反应明显减弱。最高强度刺激时，Adelta 刺激的反应减弱两周，较弱的 Adelta 刺激减弱五周。在趾部（注射部位远端）刺激时，用 5ng 或 50ng RTX 处理后 7-8 周，Adelta 反应明显减弱。相比之下，用 RTX 处理 5 周后，C 纤维刺激的反应基本正常。在纤维丧失和恢复期间，当行为最大程度减弱时，背根神经节（DRG）中的神经再生分子标志物（ATF3 和甘丙肽）上调，但伤害性活动的标志物（脊髓中的 c-Fos 和 DRG 中的 MCP-1），虽然在 RTX 治疗后立即诱导，但恢复正常。
外周 RTX 治疗后行为恢复与 TRPV1 表达的 Adelta 和 C 纤维的再生以及分子标志物的持续表达有关。红外激光刺激可能是评估 Adelta 纤维在疼痛和疼痛控制中的行为作用的有价值的工具。
