Yeomans D C, Cooper B Y, Vierck C J
University of Florida College of Medicine, Department of Neuroscience and Center for Neurobiological Sciences, Gainesville, Florida, USA.
Pain. 1996 Aug;66(2-3):253-63. doi: 10.1016/0304-3959(96)03082-5.
Despite evidence that systemic morphine preferentially attenuates second pain sensations that are presumed to result from activation of unmyelinated (C) nociceptors, most animal models of nociception elicit sensations that result from or are dominated by activation of myelinated (A-delta) nociceptors. Therefore, methods were developed to directly compare the effects of morphine on late (second) pain sensations and early onset (first) pain sensations in an animal model. In order to establish appropriate stimulus parameters, human psychophysical experiments compared characteristics of sensations evoked by brief (pulsed) thermal stimulation and ramp-and-hold thermal stimulation. Brief (500 msec) contact of a pre-heated thermode with the skin produced late pain sensations with peripheral conduction velocities in the range of C afferents, as estimated by latencies from stimulation of proximal and distal sites on the leg. The sensations evoked by brief contact increased with successive contacts (pulses) at 0.4 Hz, demonstrating temporal summation of sensation intensity. Pretreatment of the skin with capsaicin enhanced the late pain sensations from pulsed stimulation. In contrast, peak sensations evoked by ramp-and-hold thermal stimulation were evoked at similar latencies from disparate sites on the leg, and capsaicin pretreatment of the skin did not increase the magnitude of these sensations. The pulsed and ramp-and-hold forms of stimulation were used in a paradigm designed to test for differential effects of systemic morphine on operant responses of non-human primates. Low doses of morphine reduced operant responding to pulsed thermal contact, while higher doses were required to affect responses to ramp-and-hold thermal stimulation. The low doses of morphine did not suppress non-nociceptive (intertrial) motor responses, indicating that motor inhibition was not responsible for the effects on escape responses to pulsed stimulation. Measurements of skin temperature 10 cm from the site of stimulation showed that morphine had no effect on baseline temperature but attenuated changes in skin temperature that were elicited by pulsed and by ramp-and-hold stimulation. This effect of morphine on skin temperature responses could not account for the reduction of operant responsivity to thermal stimulation. These results support previous findings that systemic morphine preferentially attenuates second pain sensations, and a new animal model of morphine-sensitive thermal nociception is established. These findings demonstrate the importance of defining the sources of afferent input and the response measures in experiments which attempt to measure antinociceptive effects of pharmacological agents.
尽管有证据表明，全身性吗啡优先减轻被认为是由无髓鞘（C类）伤害感受器激活所导致的第二痛觉，但大多数伤害感受的动物模型所引发的痛觉是由有髓鞘（A-δ类）伤害感受器激活所引起或主导的。因此，人们开发了一些方法，以在动物模型中直接比较吗啡对晚期（第二）痛觉和早期发作（第一）痛觉的影响。为了确定合适的刺激参数，人体心理物理学实验比较了短暂（脉冲式）热刺激和斜坡-保持热刺激所诱发的痛觉特征。预热的热刺激器与皮肤短暂（500毫秒）接触会产生晚期痛觉，根据腿部近端和远端部位刺激的潜伏期估计，其外周传导速度在C类传入神经的范围内。短暂接触所诱发的痛觉会随着以0.4赫兹的频率连续接触（脉冲）而增强，表明痛觉强度存在时间总和效应。用辣椒素预处理皮肤可增强脉冲刺激所产生的晚期痛觉。相比之下，斜坡-保持热刺激所诱发的峰值痛觉在腿部不同部位的潜伏期相似，并且皮肤的辣椒素预处理并未增加这些痛觉的强度。脉冲式和斜坡-保持式刺激形式被用于一种范式中，旨在测试全身性吗啡对非人灵长类动物操作性反应的不同影响。低剂量的吗啡会减少对脉冲热接触的操作性反应，而需要更高剂量才能影响对斜坡-保持热刺激的反应。低剂量的吗啡不会抑制非伤害性（试验间期）运动反应，这表明运动抑制并非对脉冲刺激逃避反应产生影响的原因。在距刺激部位10厘米处测量皮肤温度表明，吗啡对基线温度没有影响，但会减弱由脉冲式和斜坡-保持式刺激所引起的皮肤温度变化。吗啡对皮肤温度反应的这种作用无法解释对热刺激操作性反应性的降低。这些结果支持了先前的研究发现，即全身性吗啡优先减轻第二痛觉，并建立了一种对吗啡敏感的热伤害感受的新动物模型。这些发现证明了在试图测量药物抗伤害感受作用的实验中，确定传入输入源和反应测量指标的重要性。
