Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision

Abstract

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

“…Additionally, the secondary hyperalgesia associated with both models is sensitive to Ca 2+ permeable AMPA/kainite receptor antagonism (Pogatzki et al, 2003;Sorkin et al, 1999;2001). We have recently demonstrated that phosokinase A and phosphokinase C, but not CaMkinase II alpha are downstream of Ca 2+ permeable non-NMDA receptors in the first degree burn model (Jones and Sorkin, 2005).…”

“…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). The present study examines the pharmacology of allodynic reversal in the first degree burn model to determine if the non-NMDA receptor initiated changes are dependent on the same second messenger systems as NMDA dependent pain models.…”

“…To this end, cyclooxygenase (COX) and nitric oxide synthase (NOS) inhibitors as well as specific VGCC blockers that are efficacious in many of the NMDA receptor sensitive models were given as spinal pretreatments prior to the thermal injury. As spinal dorsal horn Ca 2+ permeable AMPA receptors seem to play a clear role in several clinically relevant pain models such as burn (Sorkin et al, 1999), post-surgical pain (Pogatzki et al, 2003) and inflammation (Sorkin, 2001;Vikman, 2008), elucidating the second messenger pathways downstream of these receptors will help us to identify relevant pharmacological targets for these pain states with the long term goal of developing analgesics tailored to a particular pain state.…”

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

“…Intrathecal pretreatment with selective antagonists joro spider toxin (JST) or philanthotoxin (PHTx) attenuates development of secondary mechanical allodynia evoked in the thermal injury model (Sorkin et al, 1999(Sorkin et al, , 2001). In addition, joro spider toxin reverses secondary mechanical allodynia in the postincision pain model (Pogatzki et al, 2003). The present study examined the effects of AMPA/KA and Ca 2ϩ -perm-AMPA/KA receptor antagonists on thermal injury-evoked secondary mechanical allodynia when given as postinjury treatments.…”

Antiallodynic and Antihyperalgesic Effects of Selective Competitive GLUK5 (GluR5) Ionotropic Glutamate Receptor Antagonists in the Capsaicin and Carrageenan Models in Rats

“…Kainate receptors are present on small diameter C-fibers, and GLU K5 receptors have been identified on dorsal root ganglion cells as well as in the spinal cord on spinothalamic tract neurons (e.g., Agrawal and Evans, 1986;Tölle et al, 1993;Furuyama et al, 1993). Nonselective AMPA/kainate receptor antagonists, including NBQX, 6-cyano-7-nitroquinoxaline-2,3-dione, and NS1209, have been shown to produce antinociception in a variety of animal models of acute and persistent pain (e.g., Jackson et al, 1995;Pogatzki et al, 2003;Blackburn-Munro et al, 2004). However, Simmons et al (1998) demonstrated that the relatively selective GLU K5 antagonist LY382884 as well as the nonselective AMPA/kainate receptor antagonists NBQX and LY293558 but not the nonselective AMPA receptor antagonist LY300164, produced antinociception in the formalin test in rats.…”