Kyrkanides Stephanos, Fiorentino Paolo M, Miller Jen-nie H, Gan Yanjun, Lai Yu-Ching, Shaftel Solomon S, Puzas J Edward, Piancino Maria G, O'Banion M Kerry, Tallents Ross H
University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Arthritis Rheum. 2007 Jun;56(6):2038-48. doi: 10.1002/art.22635.
To evaluate opioid receptor function as a basis for novel antinociceptive therapy in arthritis.
We induced human mu-opioid receptor (HuMOR) expression in arthritic joints of mice, using the feline immunodeficiency virus (FIV) vector, which is capable of stably transducing dividing, growth-arrested, and terminally differentiated cells. Male and female Col1-IL-1beta(XAT)-transgenic mice developed on a C57BL/6J background and wild-type littermates were studied.
A single injection of FIV(HuMOR) into the temporomandibular joints of Col1-IL-1beta(XAT)-transgenic mice 1 week prior to induction of arthritis prevented the development of orofacial pain and joint dysfunction, and reduced the degree of histopathologic abnormality in the joint. In addition, FIV(HuMOR) prevented the attendant sensitization of trigeminal sensory neurons and activation of astroglia in brainstem trigeminal sensory nuclei. These effects were mediated by the transduction of primary sensory neurons via transport of FIV vectors from peripheral nerve endings to sensory ganglia, as evidenced by HuMOR expression in neuronal cell bodies located in the trigeminal ganglia, as well as in their proximal and distal nerve branches located in the main sensory and subnucleus caudalis of the brainstem and joints, respectively. The presence of MOR ligands predominantly in the descending trigeminal nucleus suggested that the observed antinociception occurred at the subnucleus caudalis. Articular chondrocytes and meniscal tissue were also infected by FIV(HuMOR), which presumably exerted an antiinflammatory effect on cartilage.
Our results indicate that prophylactic therapy with MOR overexpression in joints can successfully prevent the development of pain, dysfunction, and histopathologic abnormalities in the joints in arthritis. These findings may provide a basis for the future development of spatiotemporally controlled antinociceptive and antiinflammatory therapy for arthritis.
评估阿片受体功能，为关节炎新型抗伤害感受治疗提供依据。
我们使用猫免疫缺陷病毒（FIV）载体在小鼠关节炎关节中诱导人μ-阿片受体（HuMOR）表达，该载体能够稳定转导分裂、生长停滞和终末分化细胞。研究了在C57BL/6J背景下培育的雄性和雌性Col1-IL-1β(XAT)转基因小鼠及其野生型同窝小鼠。
在诱导关节炎前1周，向Col1-IL-1β(XAT)转基因小鼠的颞下颌关节单次注射FIV(HuMOR)可预防口面部疼痛和关节功能障碍的发生，并减轻关节组织病理学异常程度。此外，FIV(HuMOR)可预防伴随的三叉神经感觉神经元敏化和脑干三叉神经感觉核中星形胶质细胞的激活。这些作用是通过FIV载体从外周神经末梢运输到感觉神经节，从而转导初级感觉神经元介导的，这在位于三叉神经节的神经元细胞体以及分别位于脑干主要感觉核和尾侧亚核以及关节的近端和远端神经分支中HuMOR的表达得到证明。MOR配体主要存在于三叉神经降核中，表明观察到的抗伤害感受发生在尾侧亚核。关节软骨细胞和半月板组织也被FIV(HuMOR)感染，这可能对软骨发挥抗炎作用。
我们的结果表明，关节中MOR过表达的预防性治疗可成功预防关节炎关节疼痛、功能障碍和组织病理学异常的发生。这些发现可能为未来开发时空可控的关节炎抗伤害感受和抗炎治疗提供依据。
