Calcium-Permeable α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/Kainate Receptors Mediate Development, but Not Maintenance, of Secondary Allodynia Evoked by First-Degree Burn in the Rat

Abstract

Intrathecal pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists blocks development of spinal sensitization in a number of pain models. In contrast, secondary mechanical allodynia evoked by thermal injury (52.5°C for 45 s) applied to the hind paw of the rat is not blocked by intrathecal pretreatment with NMDA receptor antagonists. It is, however, blocked by antagonists to the non-NMDA, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) and calciumpermeable AMPA/KA receptors. These findings suggest a role for these receptors in the development of spinal sensitization. The present study used the same thermal injury model to assess the effects of the AMPA/KA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and specific calcium-permeable AMPA/KA receptor antagonists philanthotoxin (PHTx) and joro spider toxin (JST) when given as postinjury treatments. Intrathecal saline injection at 5 and 30 min postinjury had no effect on thermal injury-evoked allodynia as measured by calibrated von Frey filaments. In contrast, 36 nmol of CNQX given at either time point reversed allodynia. Intrathecal 13 nmol of PHTx or 9 nmol of JST (higher doses than that required for pretreatment) reversed allodynia at the 5-min time point, but neither drug was antiallodynic at the 30-min time point. Thus, secondary mechanical allodynia in this model is not maintained by calcium-permeable AMPA/KA receptors, but instead requires activation of calcium-impermeable AMPA/KA receptors. This finding supports a role for AMPA/KA receptor function in responses occurring during spinal sensitization.Peripheral inflammation and tissue injury induce sensitization of spinal cord neurons and enhance spinal nociceptive transmission (Dickenson and Sullivan, 1987;Abram and Yaksh, 1994;Traub, 1997). Behavioral correlates of spinal sensitization include secondary mechanical allodynia, an increased sensitivity to innocuous stimuli in a region adjacent to or distinct from the site of injury. Activation of N-methyl-D-aspartate (NMDA) receptors and subsequent calcium influx are thought to be early and necessary steps in the induction of spinal sensitization and resultant enhanced pain states (Murray et al., 1991;Mao et al., 1992;Yamamoto and Yaksh, 1992b). Accordingly, intrathecal administration of NMDA receptor antagonists has been shown to block both electrophysiological and behavioral manifestations of spinal sensitization (Woolf and Thompson, 1991;Dougherty et al., 1992). It is now apparent, however, that ␣-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid or kainite (AMPA/KA) receptors can also play a significant role in this stage of nociceptive processing.The AMPA receptor is composed of GLUR1-GLUR4 subunits, whereas the kainite receptor is composed of GLUR5-GLUR7, KA1, and K2 subunits. Both are permeable to monovalent sodium and potassium ions (Keinanen et al., 1990) and mediate the majority of monosynaptic current produced by glutamate release from primary afferent terminals. Recent studies show that ac...

Secondary hyperalgesia in the rat first degree burn model is independent of spinal cyclooxygenase and nitric oxide synthase

“…Work within our group indicates that intrathecal administration of antagonists to a subtype of non-NMDA receptor, Ca 2+ permeable AMPA/kainate receptors, blocks or reverses secondary mechanical allodynia in a first degree burn model in which NMDA receptor antagonists have no effect (Jones and Sorkin, 2004;Nozaki-Taguchi and Yaksh, 2002a;Sorkin et al, 1999;2001). Similar experiments using a paw incision model of post-operative pain demonstrate the same NMDA receptor independence for the area of primary hyperalgesia ) and a dependence on Ca 2+ permeable AMPA/ kainite, but not NMDA receptors for the area of secondary hyperalgesia (Pogatzki et al, 2003).…”

Ionotropic Glutamate Receptors in Spinal Nociceptive Processing

“…Inhibition of spinal AMPARs reversibly abolishes already established secondary hyperalgesia and sensitization of DH neurons in various inflammatory, neuropathic, postoperative and burn injury models of pain hypersensitivity [134,159,217,220,243,[270][271][272][273][274][275]. Interestingly, pain hypersensitivity in postoperative pain, which is essentially insensitive to NMDAR antagonism, is transiently reversed by posttreatment spinal administration of antagonists of Ca 2+ -permeable AMPARs [271].…”

“…Mechanical allodynia induced by burn injury and mechanical and thermal hyperalgesia induced by hindpaw carrageenan injection are prevented by intrathecal antagonists of Ca 2+ -permeable AMPARs, whereas such antagonists do not affect the late phase of the formalin test or mechanical allodynia induced by spinal nerve ligation [136,220,221].…”

Below Level Central Pain Induced by Discrete Dorsal Spinal Cord Injury

“…Ipsilateral and contralateral behavioral data were analyzed individually. In the initial experiments to determine the optimal dorsal root combination to avulse, group differences were analyzed by comparing area under the curve (AUC), as previously described by Jones and Sorkin ( Jones and Sorkin, 2004). AUC values were calculated from absolute threshold values, from 0 up to the threshold response of each animal across time.…”