Ossipov M H, Bian D, Malan T P, Lai J, Porreca F
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson 85724, USA.
Pain. 1999 Feb;79(2-3):127-33. doi: 10.1016/s0304-3959(98)00187-0.
Tactile allodynia and thermal hyperalgesia, two robust signs of neuropathic pain associated with experimental nerve injury, have been hypothesized to be mechanistically distinguished based on (a) fiber types which may be involved in the afferent input, (b) participation of spinal and supraspinal circuitry in these responses, and (c) sensitivity of these endpoints to pharmacological agents. Here, the possibility that nerve-injury induced tactile allodynia and thermal hyperalgesia may be mediated via different afferent fiber input was tested by evaluating these responses in sham-operated or nerve-injured (L5/L6) rats before or after a single systemic injection of resiniferatoxin (RTX), an ultrapotent analogue of the C-fiber specific neurotoxin, capsaicin. Tactile allodynia, and three measures of thermal nociception, tail-flick, paw-flick and hot-plate responses, were determined before and at various intervals for at least 40 days after RTX injection. Nerve-injured, but not sham-operated, rats showed a long-lasting tactile allodynia and thermal hyperalgesia (paw-flick) within 2-3 days after surgery; responses to other noxious thermal stimuli (i.e., tail-flick and hot-plate tests) did not distinguish the two groups at the stimulus intensities employed. RTX treatment resulted in a significant and long-lasting (i.e. essentially irreversible) decrease in sensitivity to thermal noxious stimuli in both sham-operated and nerve-injured rats; thermal hyperalgesia was abolished and antinociception produced by RTX. In contrast, RTX treatment did not affect the tactile allodynia seen in the same nerve-injured rats. These data support the concept that thermal hyperalgesia seen after nerve ligation, as well as noxious thermal stimuli, are likely to be mediated by capsaicin-sensitive C-fiber afferents. In contrast, nerve-injury related tactile allodynia is insensitive to RTX treatment which clearly desensitizes C-fibers and, therefore such responses are not likely to be mediated through C-fiber afferents. The hypothesis that tactile allodynia may be due to inputs from large (i.e. A beta) afferents offers a mechanistic basis for the observed insensitivity of this endpoint to intrathecal morphine in this nerve-injury model. Further, these data suggest that clinical treatment of neuropathic pains with C-fiber specific agents such as capsaicin are unlikely to offer significant therapeutic benefit against mechanical allodynia.
触觉异常性疼痛和热痛觉过敏是与实验性神经损伤相关的两种典型神经病理性疼痛症状，据推测，它们在机制上存在差异，具体基于以下几点：(a) 可能参与传入输入的纤维类型；(b) 脊髓和脊髓上神经回路在这些反应中的参与情况；(c) 这些终点对药理剂的敏感性。在此，通过评估假手术或神经损伤（L5/L6）大鼠在单次全身注射树脂毒素（RTX，一种C纤维特异性神经毒素辣椒素的超强力类似物）之前或之后的这些反应，来测试神经损伤诱导的触觉异常性疼痛和热痛觉过敏是否可能通过不同的传入纤维输入介导。在RTX注射之前以及注射后至少40天的不同时间间隔，测定触觉异常性疼痛以及热伤害感受的三项指标：甩尾、爪部甩动和热板反应。神经损伤但未进行假手术的大鼠在手术后2 - 3天内出现了持久的触觉异常性疼痛和热痛觉过敏（爪部甩动）；在所采用的刺激强度下，对其他有害热刺激（即甩尾和热板试验）的反应并未区分两组大鼠。RTX处理导致假手术和神经损伤大鼠对热有害刺激的敏感性显著且持久（即基本不可逆）降低；热痛觉过敏被消除，RTX产生了抗伤害感受作用。相比之下，RTX处理并未影响同一神经损伤大鼠中出现的触觉异常性疼痛。这些数据支持了这样一种观点，即神经结扎后出现的热痛觉过敏以及有害热刺激，可能由辣椒素敏感的C纤维传入介导。相比之下，与神经损伤相关的触觉异常性疼痛对RTX处理不敏感，而RTX明显使C纤维脱敏，因此这种反应不太可能通过C纤维传入介导。触觉异常性疼痛可能源于大（即Aβ）传入纤维输入的假设，为该神经损伤模型中此终点对鞘内吗啡不敏感提供了机制基础。此外，这些数据表明，用辣椒素等C纤维特异性药物对神经病理性疼痛进行临床治疗，不太可能对机械性异常性疼痛提供显著的治疗益处。
