Zylka Mark J, Sowa Nathaniel A, Taylor-Blake Bonnie, Twomey Margaret A, Herrala Annakaisa, Voikar Vootele, Vihko Pirkko
Department of Cell and Molecular Physiology, UNC Neuroscience Center, University of North Carolina, CB #7545, Chapel Hill, NC 27599, USA.
Neuron. 2008 Oct 9;60(1):111-22. doi: 10.1016/j.neuron.2008.08.024.
Thiamine monophosphatase (TMPase, also known as fluoride-resistant acid phosphatase) is a classic histochemical marker of small-diameter dorsal root ganglia neurons. The molecular identity of TMPase is currently unknown. We found that TMPase is identical to the transmembrane isoform of prostatic acid phosphatase (PAP), an enzyme with unknown molecular and physiological functions. We then found that PAP knockout mice have normal acute pain sensitivity but enhanced sensitivity in chronic inflammatory and neuropathic pain models. In gain-of-function studies, intraspinal injection of PAP protein has potent antinociceptive, antihyperalgesic, and antiallodynic effects that last longer than the opioid analgesic morphine. PAP suppresses pain by functioning as an ecto-5'-nucleotidase. Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. Our studies reveal molecular and physiological functions for PAP in purine nucleotide metabolism and nociception and suggest a novel use for PAP in the treatment of chronic pain.
硫胺素单磷酸酶（TMPase，也称为耐氟酸性磷酸酶）是小直径背根神经节神经元的经典组织化学标志物。TMPase的分子身份目前尚不清楚。我们发现TMPase与前列腺酸性磷酸酶（PAP）的跨膜异构体相同，PAP是一种分子和生理功能未知的酶。然后我们发现PAP基因敲除小鼠的急性疼痛敏感性正常，但在慢性炎症和神经性疼痛模型中敏感性增强。在功能获得性研究中，脊髓内注射PAP蛋白具有强大的镇痛、抗痛觉过敏和抗异常性疼痛作用，且持续时间比阿片类镇痛药吗啡更长。PAP通过作为胞外5'-核苷酸酶发挥作用来抑制疼痛。具体而言，PAP将细胞外单磷酸腺苷（AMP）去磷酸化为腺苷，并激活脊髓背角的A1-腺苷受体。我们的研究揭示了PAP在嘌呤核苷酸代谢和痛觉感受中的分子和生理功能，并提示PAP在慢性疼痛治疗中的新用途。
