Remeniuk Bethany, Sukhtankar Devki, Okun Alec, Navratilova Edita, Xie Jennifer Y, King Tamara, Porreca Frank
Department of Cancer Biology, Arizona Cancer Center, University of Arizona, Tucson, AZ, USA Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA Department of Biomedical Sciences, College of Osteopathic Medicine, Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, USA.
Pain. 2015 Oct;156(10):1864-1873. doi: 10.1097/j.pain.0000000000000218.
Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens (NAc) shell was observed after peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive-driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release, was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared with sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) μ-opioid receptors (MORs). The rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.
癌症诱发的骨痛被描述为隐痛、持续的疼痛。通过在大鼠胫骨内注射乳腺癌细胞来表征持续性骨癌疼痛。癌症导致了时间依赖性的骨重塑和触觉超敏反应，但没有自发退缩。在对荷瘤大鼠进行外周神经阻滞（PNB）后，观察到条件性位置偏爱（CPP）以及伏隔核（NAc）壳中的多巴胺（DA）释放增强，这揭示了伤害性驱动的持续性疼痛。口服双氯芬酸可逆转肿瘤诱导的触觉超敏反应，但不能阻断PNB诱导的CPP或NAc DA释放。预先皮下植入吗啡丸可阻断肿瘤诱导的触觉超敏反应以及PNB诱导的CPP和NAc DA释放。在假手术大鼠中，吗啡使NAc DA释放适度但持续增加。相比之下，与假手术吗啡处理的大鼠相比，吗啡使荷瘤大鼠的NAc DA释放瞬时增加了5倍。通过不可逆地阻断喙前扣带回皮质（rACC）的μ-阿片受体（MOR）来测试这种增加的NAc DA释放是否反映了疼痛缓解的奖赏作用。rACC MOR阻断可防止吗啡诱导的荷瘤大鼠NAc DA释放瞬时增加，但不影响假手术动物中吗啡诱导的效应。与临床经验一致，持续性癌症疼痛可通过吗啡控制，但不能通过逆转诱发的超敏反应的双氯芬酸剂量来控制。此外，通过阻断rACC MOR，吗啡的内在奖赏作用可与癌症疼痛缓解的奖赏作用分离。这种方法允许对持续性癌症疼痛进行机制和治疗评估，可能具有转化相关性。
