Bian D, Ossipov M H, Ibrahim M, Raffa R B, Tallarida R J, Malan T P, Lai J, Porreca F
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Brain Res. 1999 Jun 12;831(1-2):55-63. doi: 10.1016/s0006-8993(99)01393-1.
The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.
在同一大鼠的脊髓（鞘内注射）和脊髓上（脑室内注射）部位共同给予吗啡会产生镇痛协同作用，这一现象可能是该药物临床镇痛效用的基础。然而，在患有外周神经损伤的动物中，鞘内注射吗啡的镇痛效力和效果会显著降低。在此，研究了脊髓/脊髓上吗啡镇痛协同作用可能的丧失以及与脊髓强啡肽含量升高的关系。腰脊髓神经结扎导致同侧腰段和骶段脊髓中强啡肽含量升高。在假手术大鼠中，脊髓上/脊髓共同给予吗啡产生协同镇痛作用，这不受鞘内注射MK-801或强啡肽A（(1-17)）抗血清的影响。在神经损伤大鼠中，鞘内注射吗啡对触觉异常性疼痛无作用，并且在没有脊髓上/脊髓镇痛协同作用的情况下，对急性伤害感受的效力减弱。强啡肽A（(1-17)）抗血清或非竞争性NMDA拮抗剂MK-801增加了鞘内注射吗啡的镇痛效力，恢复了脊髓上/脊髓吗啡镇痛协同作用，并引发了与剂量相关的鞘内注射吗啡抗痛觉过敏作用。这些药物单独不表现出镇痛或抗痛觉过敏活性，并且不改变假手术动物中的吗啡作用。脊髓/脊髓上镇痛协同作用的丧失以及脊髓吗啡缺乏抗痛觉过敏活性似乎是由于神经损伤后多个脊髓节段强啡肽升高所致。升高的强啡肽的病理作用可能直接或间接调节NMDA受体，导致脊髓上/脊髓吗啡协同作用丧失，因此可能解释了吗啡在周围神经病变中临床镇痛效果降低的原因。
