dizocilpine-maleate and Pain--Postoperative

In previous animal studies, preemptive treatments with N-methyl-d-aspartate (NMDA) antagonists were ineffective at preventing incision-induced allodynia. It is very likely that the model was not clinically relevant for testing treatment effects on postoperative pain. The beneficial effects of preemptive treatment can be verified only by treatments with a pharmacologically proven effect in a specific pain type or animal model. We previously showed that NMDA receptor antagonists effectively alleviate enhanced mechanical hyperalgesia after plantar incision in adult rats that had been given an intraplantar injection of carrageenan as neonates. Here, using this modified model, we tested the efficacy of preemptive treatment with the NMDA antagonist MK-801.. We injected rat pups subcutaneously with 0.25% carrageenan or saline in the plantar surface of one hindpaw on postnatal day 1. On postnatal day 50, rats were killed and the ipsilateral side of the lumbar spinal cords were harvested for biochemical analysis of the expression of NR2A and NR2B at baseline, 2 hours, 4 hours, 8 hours, and 24 hours after plantar incision (n = 5 per group for each time point). For pharmacological study, rats were allocated into one of the following groups: 1 intrathecal injection of 40 nmol MK-801 15 minutes before plantar incision, 1 intrathecal injection 30 minutes after plantar incision, or 2 injections of 20 nmol or 40 nmol given at 15 minutes and 60 minutes after plantar incision (n = 10 per group for neonatally saline-treated and 12 for carrageenan-treated rats). Paw withdrawal thresholds were measured with von Frey filaments, and weight-bearing percentages were measured hourly after plantar incision.. Expressions of NMDA receptor subunits NR2A and NR2B were increased maximally 4 hours postoperatively and were significantly greater in carrageenan-treated rats than in saline-treated rats. Tests of pain sensitivity showed that MK-801 significantly alleviated the incision-induced mechanical hyperalgesia and increased weight-bearing percentage on the injured paw in carrageenan-treated rats. However, preincisional treatment was not superior to postincisional treatment as assessed during the 6-hour postoperative observation period. Groups with 2 successive postoperative injections exhibited prolonged analgesic effects. Only the group that received 2 postoperative injections and increased total dosage had improved analgesic indices.. Under conditions of proven analgesic action of an NMDA antagonist, we demonstrated that preincisional treatment is not more beneficial than postincisional treatment for postoperative pain relief in the modified animal model. Increasing the duration of administration and/or total dosage had an incremental analgesic effect in comparison with a single injection.

Topics: Analgesia; Animals; Animals, Newborn; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Male; Pain Measurement; Pain, Postoperative; Pregnancy; Preoperative Care; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Various common surgeries such as thoracotomy and inguinal hernia repair involve essential prolonged tissue retraction, often causing persistent postoperative pain. A new model was developed to mimic this clinical scenario, whereby skin/muscle incision and retraction (SMIR) in the medial thigh evoked persistent postoperative pain (Flatters (2008) [Pain 135:119-130]). This study examines the response of SMIR-evoked mechanical hypersensitivity to analgesic standards commonly used as positive controls in behavioural pain studies. Rats were anaesthetised, the skin and superficial muscle of the medial thigh was then incised and retracted for 1h. In separate experiments, morphine, gabapentin and MK-801 were intraperitoneally administered to SMIR-operated rats, at maximally tolerated doses, on postoperative day 9-13. Mechanical hypersensitivity was measured by withdrawal responses to von Frey stimulation of the plantar hindpaws. Morphine (6mg/kg) and gabapentin (100mg/kg) elicited an almost complete reversal of SMIR-evoked mechanical hypersensitivity. In contrast, MK-801 (0.1mg/kg) did not affect SMIR-evoked mechanical hypersensitivity. Contralateral hindpaw responses to von Frey stimulation were unaffected by SMIR surgery or any drug treatment. In conclusion, the SMIR model displays persistent mechanical hypersensitivity that is reversible by morphine or gabapentin treatment. As previously demonstrated, SMIR-evoked pain is not driven by neuronal damage and these data show that NMDA receptor activation does not play a role in the maintenance of SMIR-evoked pain. This study further demonstrates the value of the SMIR model as a tool to understand persistent postoperative/postsurgical pain mechanisms and evaluate potential treatments.

Topics: Amines; Analgesics; Animals; Chronic Disease; Cyclohexanecarboxylic Acids; Dermatologic Surgical Procedures; Disease Models, Animal; Dizocilpine Maleate; Gabapentin; gamma-Aminobutyric Acid; Hindlimb; Hyperalgesia; Male; Morphine; Muscle, Skeletal; Pain Measurement; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Touch

Further understanding of pathophysiology of postoperative acute pain is necessary for its better management. The methodology of current threshold (CT) determination by using sine-wave stimuli at 3 frequencies has been used to selectively and quantitatively analyze the function of the subsets of fibers (i.e., frequency of 5, 250, and 2000Hz recruits C-, Adelta-, and Abeta-fibers, respectively). This study investigated how surgical incision would affect the CTs, and then assessed the efficacy of intrathecal pharmacotherapy. The CT required to evoke a paw withdrawal response was assessed over time at stimulus frequencies of 5Hz (CT5), 250Hz (CT250), and 2000Hz (CT2000) in rats that had undergone surgical incision of the plantar skin and muscle. The CTs at all frequencies significantly decreased immediately after the incision. The decreased thresholds gradually recovered during the first week post-surgery. CT5 and CT250 (but not CT2000) remained significantly low even on day 7 post-surgery. Morphine at 5microg/10microL i.t. significantly reversed CT5 and CT250. NBQX (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]/kainate receptor antagonist) at 1.9 or 3.8microg/10microL i.t. significantly increased the thresholds over the pre-surgery threshold levels at all frequencies. MK-801 (N-methyl d-aspartate [NMDA] receptor antagonist) up to 13.5microg/10microL i.t. did not significantly affect CTs at any frequencies. In conclusion, a broad spectrum of sensory fibers (Abeta, Adelta, and C) is sensitized at the spinal and/or peripheral level in the postoperative acute pain state. Spinal AMPA/kainate receptors but not NMDA receptors play a significant role in this sensitization.

Topics: Animals; Dizocilpine Maleate; Foot; Infusions, Parenteral; Male; Models, Animal; Morphine; Narcotics; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Pain Threshold; Pain, Postoperative; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Subarachnoid Space

Surgery commonly causes pain and neural plasticity that are unique compared to other persistent pain problems. To more precisely study central sensitization and plasticity, we examined the role of ionotropic EAA receptors in dorsal horn neuron sensitization early after incision. Sensitization, in the form of increased background activity, increased mechanosensitivity or pinch receptive field expansion, was induced by plantar incision 1 h later in 30 neurons. (+)-5-Methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) or 1 mM 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX) was administered through a microdialysis fiber to block NMDA and nonNMDA EAA receptors, respectively. Dorsal horn neuron sensitization was reexamined 1 h later. Spinal administration of NBQX blocked AMPA-induced excitation but did not affect excitation by NMDA. NBQX decreased background activity in the neurons that developed sustained increased activity after incision. The median decrease caused by NBQX was from 2.3 to 0.0 imp/s. Spinal administration of 5 mM MK-801 blocked NMDA-induced excitation but did not affect excitation by AMPA. The median change (from 2.6 to 1.1 imp/s) in background activity increased by incision was not significantly affected by MK-801. The responses to mechanical stimuli were enhanced after incision in wide dynamic range (WDR) neurons. NBQX eliminated these responses but MK-801 had no effect. The pinch receptive field (RF) expansion into uninjured areas of the paw and hindquarters occurred after incision. Only 1 of 13 neurons exhibited RF expansion after spinal NBQX administration; 9 of 12 neurons had RF expansion remaining after MK-801. Thus, nonNMDA receptors are critical and NMDA-independent factors influence the increased responsiveness of dorsal horn neurons that occur early after incision.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Male; N-Methylaspartate; Neuronal Plasticity; Pain, Postoperative; Physical Stimulation; Posterior Horn Cells; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Postoperative pain significantly impacts patient recovery. However, postoperative pain management remains suboptimal, perhaps because treatment strategies are based mainly on studies using inflammatory pain models. We used a recently developed mouse model of incisional pain to investigate peripheral and spinal mechanisms contributing to heat hyperalgesia after incision. Behavioral experiments involving TRPV1 KO mice demonstrate that, as previously observed in inflammatory models, TRPV1 is necessary for heat (but not mechanical) hyperalgesia after incision. However, in WT mice, neither the proportion of TRPV1 immunoreactive neurons in the DRG nor the intensity of TRPV1 staining in the sciatic nerve was different from that in controls up to 4 days after incision. This result was corroborated by immunoblot analysis of sciatic nerve in rats subjected to an incision, and is distinct from that following inflammation of the rat hind paw, a situation in which TRPV1 expression levels in sciatic nerve increases. In the absence of heat exposure, spinal c-Fos staining was similar between incised TRPV1 KO and WT mice. However, differences in c-Fos staining between heat exposed TRPV1 KO and WT mice after incision suggest that the incision-mediated enhancement of heat-evoked signaling to the spinal cord involves a TRPV1-dependent mechanism. Finally, heat hyperalgesia after incision was reversed by antagonism of spinal non-NMDA receptors, unlike inflammatory hyperalgesia, which is mediated via NMDA receptors . Thus, TRPV1 is important for the generation of thermal hyperalgesia after incision. Our observations suggest that all experimental pain models may not be equally appropriate to guide the development of postoperative pain therapies.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Hot Temperature; Hyperalgesia; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurogenic Inflammation; Nociceptors; Pain, Postoperative; Physical Stimulation; Proto-Oncogene Proteins c-fos; Quinoxalines; Skin; TRPV Cation Channels

Drugs that block spinal excitatory amino acid receptor activation may prevent pain after surgery. The authors previously studied the effect of excitatory amino acid receptor antagonists after incision. In the present study, we examined the role of N-methyl-d-aspartate (NMDA), non-NMDA, and metabotropic glutamate receptors (mGluRs) on the development of pain behavior after plantar incision.. Rats with lumbar intrathecal catheters were anesthetized with halothane. Fifteen minutes before an incision was made, drug [40 nmol MK-801; 20 nmol NBQX; or 200 nmol (+)-MCPG] or vehicle was injected intrathecally followed by an infusion of the same drug for 75 min. Withdrawal thresholds to calibrated von Frey filaments applied adjacent to the wound and response frequencies to a blunt mechanical stimulus applied directly to the wound were measured before incision and 1, 2, 4, and 6 h after incision and then once daily for 6 days.. Preincision treatments with antagonists against the NMDA (MK-801) and group I and II metabotropic receptors [(+)-MCPG] did not inhibit the development of mechanical hyperalgesia caused by incision. Preincision treatment with the non-NMDA receptor antagonist NBQX increased withdrawal thresholds at 1 and 2 h and on postoperative day 1 compared with the vehicle group; response frequencies were reduced 1 and 2 h after incision and on postoperative day 2 (P < 0.05). In an additional group, postincision treatment with NBQX was similar to preincision treatment.. Spinal NMDA and mGluR antagonists may not be useful for preventing postsurgical pain. Spinal non-NMDA receptor antagonists reduced pain behaviors, but a preventive effect using preincision treatment was not apparent.

Topics: Analgesia; Anesthesia, Inhalation; Anesthetics, Inhalation; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Foot; Halothane; Injections, Spinal; Male; Motor Activity; Pain, Postoperative; Quinoxalines; Rats; Rats, Sprague-Dawley

Evidence from experiments by others indicates an important role for excitatory amino acids activating spinal n-methyl-d-aspartate (NMDA) receptors in models of persistent pain. The purpose of this study was to examine the effect of intrathecal (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801), a noncompetitive NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (AP5), a competitive NMDA receptor antagonist, and N-G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on pain behaviors in a rat model of postoperative pain.. Rats with intrathecal catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound, response frequency to application of a nonpunctate stimulus applied directly to the wound, and nonevoked pain behaviors were measured before and after intrathecal administration of MK-801 or AP5. The effect of intrathecal L-NAME on mechanical hyperalgesia was also examined.. Mechanical hyperalgesia increased and was persistent after plantar incision and was not decreased by intrathecal administration of 4, 14, or 40 nmol MK-801 or 10 nmol AP5. Only the greatest dose of AP5, 30 nmol, caused a small decrease in punctate and nonpunctate hyperalgesia. Intrathecal L-NAME had no effect. Neither intrathecal MK-801 nor intrathecal AP5 affected nonevoked pain behaviors. The greatest doses caused motor deficits.. Unlike intrathecal and systemic morphine, intrathecal NMDA receptor antagonists did not modify pain behaviors in this rat model of postoperative pain. These data suggest that NMDA receptors do not play an important role in the maintenance of postoperative pain behaviors and that NMDA receptor antagonists, administered spinally by themselves during the postoperative period, will not be useful for the treatment of postoperative pain in humans.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Male; Motor Activity; NG-Nitroarginine Methyl Ester; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord