Secondary hyperalgesia, an exaggerated response to stimuli applied to undamaged tissue surrounding an injury, is a common consequence of tissue injury and inflammation. It is well established that the etiology of secondary hyperalgesia is sensitization of central neurons but the exact mechanism and its role in certain clinical pain states is unclear. In the present experiments, we studied responses to punctate and non-punctate mechanical stimuli and to heat applied to the plantar aspect of the hindpaw remote to an incision in the gastrocnemius region of the rat hindlimb. Median withdrawal thresholds to von Frey filaments were reduced 2h after incision of skin, fascia and muscle (gastrocnemius incision, n = 9) and remained reduced through postoperative day 6 (p < 0.05 vs sham). Only a transient reduction in withdrawal threshold occurred after incision of skin and fascia (skin incision, n = 10). No enhanced responsiveness to blunt mechanical stimulation or reduction in withdrawal latency to heat was present after gastrocnemius incision (p > 0.05 vs sham, n = 9 each group). Reduced withdrawal thresholds were blocked by i.t. administration of morphine and by local anesthetic injection at the test site 2h and 2 days after gastrocnemius incision. These pharmacological data provide evidence that reduced withdrawal thresholds after gastrocnemius incision are nociceptive behaviors indicating persistent secondary hyperalgesia. Because the behaviors have a similar time course to secondary hyperalgesia in postoperative patients, the model will be useful to evaluate the mechanisms for secondary mechanical hyperalgesia after incision, its pharmacological characteristics and its potential role in persistent postoperative pain.

Secondary mechanical hyperalgesia has been demonstrated in postoperative patients indicating that central sensitization occurs after surgery. However, the underlying mechanisms are unknown. Here, we studied the role of spinal N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors for pain behaviors indicating secondary hyperalgesia caused by gastrocnemius incision in the rat. We further determined if Ca(2+) permeable AMPA/kainate receptors are important for secondary hyperalgesia after gastrocnemius incision and for pain behaviors indicating primary hyperalgesia and guarding behavior after plantar incision. Withdrawal thresholds (WTs) to punctate mechanical stimuli were assessed by applying calibrated monofilaments to the plantar hind paw before gastrocnemius incision. WTs were tested again 2 h after gastrocnemius incision and again after intrathecal (IT) injection of either dizocilpine maleate (MK-801), 2-amino-5-phosphonovaleric acid (AP5), 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX), or Joro spider toxin (JSTX). The doses used were: MK-801 (vehicle, 15, 30, 40 nmol), AP5 (vehicle, 10, 30 nmol), NBQX (vehicle, 5, 10 nmol), and JSTX (vehicle, 2, 5, 9 nmol). In the same rats, WTs were tested on postoperative day 2 before and after the same drugs were injected again. In other rats, WTs to monofilaments and response frequencies to a non-punctate mechanical stimulus or guarding behaviors were determined before, 1 h after plantar incision was made, and assessed again after JSTX (9 nmol or vehicle) was administered IT. Secondary mechanical hyperalgesia after gastrocnemius incision was dose-dependently blocked by NBQX but was only marginally affected by AP5 or MK-801. Only secondary mechanical hyperalgesia was reversed by JSTX; primary mechanical hyperalgesia and guarding behavior were unchanged. These results indicate that spinal sensitization contributing to behaviors for secondary hyperalgesia after incision requires Ca(2+) permeable AMPA/kainate receptors. The data further demonstrate that behaviors for secondary mechanical hyperalgesia after incision can be inhibited without affecting behaviors for primary mechanical hyperalgesia and guarding. Mechanisms for central sensitization causing secondary hyperalgesia in postoperative patients may therefore be separated from spontaneous pain and hyperalgesia that arises adjacent to the area of the incision.

Secondary mechanical hyperalgesia has been demonstrated in postoperative patients indicating that central sensitization occurs after surgery. However, the underlying mechanisms are unknown. Here, we studied the role of spinal AMPA/kainate receptors for pain behaviors indicating secondary hyperalgesia caused by gastrocnemius incision in the rat. These were reduced by NBQX, a selective antagonist of AMPA/kainate receptors. However, administration of NMDA receptor antagonists caused no or only a modest decrease in behaviors for secondary hyperalgesia but produced associated motor deficits and supraspinal side effects. We further determined that only secondary mechanical hyperalgesia was reversed by JSTX, a selective antagonist of calcium-permeable AMPA receptor; primary mechanical hyperalgesia and guarding behavior were unchanged. These findings indicate that JSTX influenced a spinal amplification process that leads to secondary hyperalgesia but does not contribute to primary hyperalgesia and guarding after incision. This amplification process likely requires Ca(2) influx through spinal AMPA/KA (but not NMDA) receptors. Behaviors for secondary mechanical hyperalgesia after incision can be inhibited without affecting primary mechanical hyperalgesia and guarding. Mechanisms for central sensitization causing secondary hyperalgesia in postoperative patients may therefore be separated from spontaneous pain and hyperalgesia that arises adjacent to the area of the incision.