Abstract：
Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.
摘要：
慢性原发性疼痛（CPP）发生在没有组织损伤的情况下，包括颞下颌关节紊乱病（TMD），纤维肌痛综合征（FMS）和肠易激综合征（IBS）。CPP通常被认为是与压力相关的慢性疼痛，并且通常在身体的不同区域表现为广泛性疼痛或合并症疼痛状况。然而,长期应激是否可直接导致CPP合并症的发展尚不清楚.在本研究中,我们在小鼠中采用了21天的异型应激范式，并检查了慢性应激是否会引起广泛的痛觉过敏，临床中CPP共病建模。我们发现慢性压力会引起焦虑和抑郁样行为，并导致在几个身体区域如口面区域持久的广泛的痛觉过敏，后爪,大腿,雌性小鼠的上背部和腹部。我们进一步发现，与对照动物相比，在14天和21天异型应激后，雌性小鼠L4-L5脊髓背角中胆囊收缩素（CCK）1受体的表达显着增加。鞘内注射CCK1受体拮抗剂CR-1505阻断了包括上背部在内的颈下体部的疼痛超敏反应，大腿,后爪和腹部。这些发现表明，慢性应激后脊髓CCK1受体的上调有助于广泛痛觉过敏发展的核心机制。并可能为临床治疗CPP提供一个潜在的新的中心靶点。
