Chronic pain and opioid receptor availability: disentangling the molecular contributions and the "chicken or the egg" dilemma.
Chronic pain and opioid receptor availability: disentangling the molecular contributions and the "chicken or the egg" dilemma.
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慢性疼痛和阿片受体可用性：解开分子贡献和“先有鸡还是先有蛋”的困境。
DOI：
10.1097/j.pain.0000000000001283
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发表时间：
2018
期刊：
影响因子：
7.4
通讯作者：
Loggia,MarcoL
中科院分区：
文献类型：
--
作者：
Loggia,MarcoL
Starting with the 1973 discovery of opioid receptor sites in the brain, 16 substantial evidence from both preclinical and clinical studies has established the endogenous opioid system as a key player in the experience and regulation of pain, both in physiological and pathological conditions. 4 An important source of this evidence has undoubtedly been in vivo molecular imaging, especially positron emission tomography (PET). For instance, through the use of [11C]-carfentanil (a selective m-opioid receptor agonist) or [11C]-or [18F]-diprenorphine (a nonselective, weak partial agonist of them-, k-, and d-opioid receptors), PET scientists have demonstrated that opioidergic neurotransmission is activated in healthy volunteers during acute pain stimulation20, 23 or during expectation of pain relief. 22 Importantly, by showing changes in opioid receptor availability in humans with different pain disorders (including central and peripheral neuropathic pain, complex regional pain syndrome, fibromyalgia, and arthritis pain5, 8–10, 12, 14, 21), molecular imaging studies have provided experimental evidence in support of a role for alterations in the opioid system as likely contributors to several clinical manifestations associated with chronic pain, including the high prevalence of psychiatric comorbidities and the large interindividual variability in the efficacy of opioid therapy. Although results from human PET studies have undeniably advanced our understanding of the opioid system’s contributions to chronic pain, their interpretation can sometimes present challenges. Some of these are to be attributed to the crosssectional nature of many of these studies, which cannot resolve the question of causality. Are the observed alterations in opioid PET signal caused by the pain condition itself, or are they predating (and perhaps predisposing to) its development? Are these changes induced by the treatment, or even by lifestyle changes (eg, in the amount of physical exercise, or in the engagement in social and other pleasurable activities) that commonly accompany a chronic pain disorder? Could they just be an epiphenomenon? In addition to the difficulty in solving the “chicken or the egg” question, inferring the exact neurobiological underpinnings of the observed PET signal changes can sometimes present some uncertainties. For instance, the reduction in opioid receptor availability that has been reported in several pain disorders has been alternatively interpreted in terms of the loss or inactivation of opioid receptors, 10 a reactive increase in opioidergic neurotransmission, competing with the exogenously administered radioligand, 21 or a combination of both. 14 Of course, having a better understanding of the biological correlates of our imaging metrics would dramatically enhance our interpretation of the results arising from the PET literature. By adopting an elegant combination of behavioral testing, in vivo and ex vivo imaging (using PET and immunohistochemistry), within a well-controlled longitudinal preclinical design, the study by Thompson et al. 19 is able to generate insights that significantly advance our understanding of the relationship between neuropathic pain and alterations in the opioid system. This wellconceived study overcomes several of the limitations that typically accompany cross-sectional human studies and ultimately aids with the interpretation of their results. First, because of the longitudinal design of their study, the authors are able to show that the reduction in opioid receptor availability can be a consequence of nerve injury itself. The brains of Sprague-Dawley rats were scanned using PET imaging and [18F] FDPN (a fluorinated analog of diprenorphine) 3 …
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