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【目的】观察慢性吗啡耐受大鼠脊髓背角 P2X4受体（P2X4 R）的表达以及鞘内注射嘌呤受体拮抗剂TNP‐ATP（P2X1‐4 R 抑制剂）和 PPADS（P2X1‐3，5‐7 R 抑制剂）对慢性吗啡耐受大鼠的影响。【方法】60只成年雄性SD 大鼠，随机分为4组（ n ＝15）：对照组（C 组）、吗啡组（M 组）、吗啡＋ TNP‐ATP 组（T 组）和吗啡＋ PPADS 组（P 组）。对照组：大鼠鞘内注射生理盐水（20μL）；M 组：大鼠鞘内注入吗啡10μg （10μL ）和生理盐水10μL ；T组：大鼠鞘内注入 TNP‐ATP 10 nmol（10μL ），半小时后注入吗啡10μg （10μL）；P 组：大鼠经鞘内置管并注入PPADS 10 nmol（10μL），半小时后注入吗啡10μg（10μL），2次／日，连续7 d 。每只大鼠于术前测定基础热痛阈，各组每次给药后测量大鼠热痛阈，d1、d3、d7最后一次测量痛阈后处死5只大鼠取脊髓背角，采用免疫组化检测 P2X4受体表达。【结果】M 组在 d1、d3的热痛阈显著高于 C 组（ P ＜0．05），随着吗啡注药天数增加，M 组热痛阈逐渐下降，d5、d7与 C 组的差异无统计学意义（ P ＞0．05）。与 M 组比较，P 组各时点热痛阈无明显差异，但 T组热痛阈虽然也呈下降趋势，但明显缓于 M 组，T 组 d5、d7的热痛阈高于 M 组，差异有统计学意义（ P ＜0．05）。与 C 组比较，M 组和 P 组在给药 d1、d3、d7大鼠脊髓背角 P2X4 R 表达上调（ P ＜0．05）。 鞘内注射 TNP‐ATP 组P2X4 R 表达明显低于 M 组和 P 组（ P ＜0．05）。 【结论】鞘内给予 TNP‐ATP 能够延缓大鼠慢性吗啡耐受的形成，其机制可能与其抑制 P2X4 R 的表达有关。“,”Objective] To observe the changes of P2X4 receptor in spinal dorsal horn and explore the effect of TNP‐ATP (P2X1‐4 R inhibitor)and PPADS(P2X1‐3 ,5‐7 R inhibitor)intrathecally administered in chronic morphine tolerance rats .[Methods] A total of 60 male adult Sprague‐Dawley rats were randomly divided into four groups ( n = 15 each) of control (C) ,morphine (M) ;TNP‐ATP + morphine (T) and PPADS + morphine (P) .The animals received intrathecal injec‐tions of morphine 10 μg(10 μL)and saline 10 μL twice daily for 7 days (T1 ~ T7 ) in group M while an equal volume of sa‐line in group C .Groups T and P received intrathecal injections of 10 nmol(10 μL) TNP‐ATP and PPADS respectively for 7 days 30 min before the same treatment in group M .We assessed basic mechanical and thermal pain threshold at 2 days pre‐operation .Pain threshold to a thermal nociceptive stimulus was measured 30 min after dosing at T 1 ~ 7 in each group . Five rats in each group were sacrificed after last dosing at 1st ,3th ,7th days and spinal cord dorsal horn removed for de‐tecting the expression of P2X4 R by immunohistochemistry .[Results] Thermal pain threshold of group M was significant‐ly higher than that of group C at day 1 and 3 ( P 0 .05) .The difference was not significantly different between groups M and P ( P > 0 .05) .Thermal pain threshold of group T decreased more slowly than that of group M .Thermal pain threshold of group T was higher than that of group M ,especially during 5 and 7d ( P < 0 .05) .The expression of P2X4 R in groups M and P was obviously higher than that of group C at day 1 ,3 and 7 . The expression of P2X4 R significantly decreased in group T after an intrathecal dose of TNP‐ATP compared with groups M and P ( P < 0 .05) .[Conclusion] Intrathecal TNP‐ATP attenuates morphine‐induced pain and suppresses spinal P2X4 R expression in rats .