Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Int Rev Neurobiol. 2010;95:227-79. doi: 10.1016/B978-0-12-381326-8.00010-7.
In animals, different types of COMT inhibitors, irrespective of their brain penetration, are pro-nociceptive in several models of acute and inflammatory pain. Similarly, COMT knock-out mice are more sensitive to nociceptive stimuli, whereas in mice over-expressing a high activity COMT variant nociceptive sensitivity is decreased. COMT knock-out mice also show altered response to opioids and stress-induced analgesia. In different rat models of neuropathic pain, the action of nitecapone is opposite: it is antinociceptive and antiallodynic. Complex actions of low COMT activity may be caused by enhanced adrenergic and dopaminergic activities that play different and even contrasting roles at different parts of the nociceptive system. Also compensatory changes in other neurotransmitters may occur. Pro-nociceptive effects seem to be caused by increased activation of peripheral adrenergic β(2)- and β(3) -receptors. Other properties of COMT inhibitors, like scavenging of oxygen and nitrogen radicals, may be important in antiallodynic effects found in neuropathic pain models. Increased number of µ-opioid receptors in certain brain areas may be responsible of enhanced opioid effects associated with a low COMT activity. In human pain studies, a low COMT activity is often associated with increased pain sensitivity in experimental pain models and with increased pre- and postoperative pain in acute clinical situations. As a rule, a simultaneous occurrence of several SNPs within the haplotype, causing low COMT activity, is more often associated with pain than any single SNP alone. In experimental pain studies, all negative findings resulted from concentrating solely on SNP rs4680 (Val158Met). Virtually all studies assessing haplotypes were able to confirm an association of a low COMT and increased pain. In chronic clinical pain, the effect of COMT polymorphisms depends on the pain conditions. Hence, in neuropathic and cancer pains, COMT activity is meaningless but in some chronic musculoskeletal pain conditions and migraine or headache low COMT activity appears to increase incidence and symptoms. A low COMT activity also increases availability of opioid receptors and may enhance opioid analgesia and adverse effects at least in cancer pains.
在动物中，不同类型的 COMT 抑制剂，无论其是否能穿透血脑屏障，在几种急性和炎症性疼痛模型中均具有致痛作用。同样，COMT 基因敲除小鼠对伤害性刺激更为敏感，而在高活性 COMT 变异体过表达的小鼠中，伤害性敏感性降低。COMT 基因敲除小鼠对阿片类药物和应激性镇痛的反应也发生改变。在不同的神经病理性疼痛大鼠模型中，尼卡地平的作用相反：它具有镇痛和抗痛觉过敏作用。低 COMT 活性的复杂作用可能是由于肾上腺素能和多巴胺能活性增强所致，这些活性在伤害性系统的不同部位发挥不同甚至相反的作用。其他神经递质也可能发生代偿性变化。致痛作用似乎是由于外周肾上腺素能β(2)-和β(3)-受体的激活增加所致。COMT 抑制剂的其他特性，如氧和氮自由基的清除，可能在神经病理性疼痛模型中发现的抗痛觉过敏作用中很重要。某些脑区µ-阿片受体数量的增加可能是与低 COMT 活性相关的阿片类药物作用增强的原因。在人类疼痛研究中，低 COMT 活性通常与实验性疼痛模型中疼痛敏感性增加以及急性临床情况下术前和术后疼痛增加相关。通常，同一单倍型内几个 SNP 的同时发生，导致低 COMT 活性，比任何单个 SNP 更常与疼痛相关。在实验性疼痛研究中，所有阴性结果均来自于仅关注 SNP rs4680（Val158Met）。实际上，评估单倍型的所有研究都能够证实低 COMT 与疼痛增加之间的关联。在慢性临床疼痛中，COMT 多态性的作用取决于疼痛状况。因此，在神经病理性疼痛和癌性疼痛中，COMT 活性无意义，但在某些慢性肌肉骨骼疼痛状况和偏头痛或头痛中，低 COMT 活性似乎会增加发生率和症状。低 COMT 活性还会增加阿片受体的可用性，并可能增强阿片类药物的镇痛作用和不良反应，至少在癌性疼痛中如此。
