Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy

Abstract

The hyperalgesia and spontaneous pain that occur following peripheral nerve injury may be related to abnormal peripheral input or altered central activity, or both. The present experiments investigated these possibilities by examining the effects of MK-801 (a non-competitive N-methyl- d-aspartate, NMDA, receptor antagonist) and bupivacaine (a local anesthetic agent) on thermal hyperalgesia and spontaneous nociceptive behaviors in rats with painful peripheral mononeuropathy. Peripheral mononeuropathy was produced by loosely ligating the rat's common sciatic nerve, a procedure which causes chronic constrictive injury (CCI) of the ligated nerve. The resulting hyperalgesia to radiant heat and spontaneous nociceptive behaviors was assessed by using a foot-withdrawal test and a spontaneous pain behavior rating method, respectively. CCI rats receiving 4 daily intraperitoneal (i.p.) MK-801 injections (0.03, 0.1, 0.3 mg/kg) beginning 15 min prior to nerve ligation exhibited less hyperalgesia (i.e., longer foot-withdrawal latencies) on days 3, 5, 7, 10, and 15 after nerve ligation as compared to those receiving saline injections. Thermal hyperalgesia also was reduced when a single MK-801 injection was given intrathecally (i.t.) onto the spinal cord lumbar segments on Day 3 after nerve ligation. This effect of postinjury MK-801 treatment was dose-dependent (2.5 – 20 nmol) and lasted for at least 48 h after injection. Moreover, i.t. injection of MK-801 (10 nmol) reliably lowered spontaneous pain behavior rating scores in CCI rats compared to those in the saline group. The spinal site of MK-801 action is situated within the caudal (probably lumbar) spinal cord, since i.t. injection of MK-801 (10 nmol) onto the spinal cord thoracic segments did not affect thermal hyperalgesia. Local anesthesia of the ligated sciatic nerve induced by a single perinerve bupivacaine injection on Day 3 after nerve ligation reliably reduced thermal hyperalgesia when tested 24 h after injection, indicating that abnormal peripheral input contributes to maintenance of neuropathic pain. While i.t. MK-801 (2.5 nmol) or local nerve anesthesia on Day 3 after nerve ligation attenuated thermal hyperalgesia for less than 48 h after injection, the combined application of MK-801 and bupivacaine extended the duration of the attenuation of thermal hyperalgesia for at least 4 days after injection. The data indicate that the central blockade of NMDA receptors and peripheral nerve anesthesia synergistically attenuate nociceptive behaviors associated with peripheral mononeuropathy. The results suggest that hyperalgesia and spontaneous pain behaviors following constrictive nerve injury may be related to both abnormal peripheral input and altered central activity involving NMDA receptor activation. These results also suggest novel approaches to the clinical management of postinjury neuropathic pain syndromes.