Treede R D, Meyer R A, Raja S N, Campbell J N
Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21205.
Prog Neurobiol. 1992;38(4):397-421. doi: 10.1016/0301-0082(92)90027-c.
Hyperalgesia after cutaneous injury can be divided into two phenomena: Primary hyperalgesia occurs at the site of injury and is characterized by hyperalgesia to mechanical and heat stimuli. Secondary hyperalgesia occurs outside the injury site and is characterized by mechanical hyperalgesia only. Hyperalgesia in inflammatory processes corresponds to primary hyperalgesia. Hyperalgesia in referred pain and neuropathic pain resembles secondary hyperalgesia (Table 3). Evidence for the latter would be strengthened if hyperalgesia to cooling stimuli, which is observed in neuropathic pain, was also demonstrated in referred pain and in secondary hyperalgesia. Some of the more likely neural mechanisms to explain primary and secondary hyperalgesia are illustrated in Fig. 8. Primary hyperalgesia to heat stimuli has a counterpart in the sensitization of peripheral nociceptors to heat stimuli (Fig. 8A), leading to similar changes in central neurons. In addition, the enlargement of the mechanical receptive field of primary afferent nociceptors to include the site of injury may account for the primary hyperalgesia to mechanical stimuli (Fig. 8B). In the literature, there are some contradictions with respect to the stimulus modalities to which hyperalgesia and sensitization occur. In spite of the well-documented sensitization of primary afferent nociceptors to heat stimuli, there are few studies on its molecular mechanisms. On the other hand, there is pharmacological evidence for a peripheral mechanism of primary mechanical hyperalgesia, but little direct evidence that nociceptors can be sensitized to mechanical stimuli by injury. This contradiction should spawn further investigations into the mechanical response properties of nociceptors and into the molecular mechanisms of heat sensitization. Secondary hyperalgesia to mechanical stimuli is likely due to the sensitization of central pain signalling neurons (CPSNs). This sensitization could involve only input from nociceptors (Fig. 8C), since mechanical pain thresholds after a cutaneous injury are of the same order as those of nociceptors. Central sensitization could also be the result of enhanced connectivity between low-threshold mechanoreceptors and CPSNs (Fig. 8D). This form of sensitization may account for the pain to light touch associated with neuropathic pain. Receptive field plasticity is a prevalent property of dorsal horn neurons and probably plays a vital role with regard to hyperalgesia. The molecular mechanisms of synaptic plasticity are currently subject to intense experimental investigation and may provide new insights on the mechanisms of pain and hyperalgesia.
原发性痛觉过敏发生在损伤部位，其特征是对机械刺激和热刺激产生痛觉过敏。继发性痛觉过敏发生在损伤部位以外，仅以机械性痛觉过敏为特征。炎症过程中的痛觉过敏与原发性痛觉过敏相对应。牵涉痛和神经性疼痛中的痛觉过敏类似于继发性痛觉过敏（表3）。如果在牵涉痛和继发性痛觉过敏中也能证明存在在神经性疼痛中观察到的对冷刺激的痛觉过敏，那么支持后者的证据将得到加强。图8展示了一些更可能解释原发性和继发性痛觉过敏的神经机制。原发性热刺激痛觉过敏与外周伤害感受器对热刺激的敏化相对应（图8A），导致中枢神经元发生类似变化。此外，初级传入伤害感受器的机械感受野扩大到包括损伤部位，这可能解释了对机械刺激的原发性痛觉过敏（图8B）。在文献中，关于发生痛觉过敏和敏化的刺激方式存在一些矛盾之处。尽管有充分的文献证明初级传入伤害感受器对热刺激的敏化，但对其分子机制的研究却很少。另一方面，有药理学证据支持原发性机械性痛觉过敏的外周机制，但几乎没有直接证据表明伤害感受器可因损伤而对机械刺激敏感。这种矛盾应该促使人们进一步研究伤害感受器的机械反应特性以及热敏化的分子机制。继发性机械性痛觉过敏可能是由于中枢疼痛信号神经元（CPSNs）的敏化所致。这种敏化可能仅涉及来自伤害感受器的输入（图8C），因为皮肤损伤后的机械痛阈值与伤害感受器的阈值处于同一水平。中枢敏化也可能是低阈值机械感受器与CPSNs之间连接增强的结果（图8D）。这种敏化形式可能解释了与神经性疼痛相关的轻触痛。感受野可塑性是背角神经元的一个普遍特性，可能在痛觉过敏方面起着至关重要的作用。突触可塑性的分子机制目前正受到深入的实验研究，可能会为疼痛和痛觉过敏的机制提供新的见解。
