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Biomedical subjects

T J Brennan

Publications and source records attributed to T J Brennan.

At least 19 recordsLinked to original sources
PubMed2000

The mammalian sodium channel BNC1 is required for normal touch sensation.

Of the vertebrate senses, touch is the least understood at the molecular level The ion channels that form the core of the mechanosensory complex and confer touch sensitivity remain unknown. However, the similarity of the brain sodium channel 1 (BNC1) to nematode proteins involved in mechanotransduction indicated that it might be a part of such a mechanosensor. Here we show that disrupting the mouse BNC1 gene markedly reduces the sensitivity of a specific component of mechanosensation: low-threshold rapidly adapting mechanoreceptors. In rodent hairy skin these mechanoreceptors are excited by hair movement. Consistent with this function, we found BNC1 in the lanceolate nerve endings that lie adjacent to and surround the hair follicle. Although BNC1 has been proposed to have a role in pH sensing, the acid-evoked current in cultured sensory neurons and the response of acid-stimulated nociceptors were normal in BNC1 null mice. These data identify the BNC1 channel as essential for the normal detection of light touch and indicate that BNC1 may be a central component of a mechanosensory complex.

Animals↗
PubMed2000

Lumbar catheterization of the subarachnoid space with a 32-gauge polyurethane catheter in the rat.

Chronic catheterization of the subarachnoid space of rats is an important tool for intrathecal drug delivery in pharmacologic investigations of pain. We describe a technique using direct lumbar insertion of a small 32-gauge polyurethane (PU) catheter without extensive surgery. Location of the catheter was confirmed with 2% lidocaine injection 1 day later, and methylene blue injection after 7-14 days. This method improved recovery of the rat after catheter implantation and reduced neurologic complications.

Animals↗
PubMed2000

Effect of pretreatment with intrathecal excitatory amino acid receptor antagonists on the development of pain behavior caused by plantar incision.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Analgesia↗
PubMed2000

Alterations in ascending dorsal horn neurons by a surgical incision in the rat foot.

BACKGROUND: Little is known about the mechanisms of pain caused by a surgical incision. The authors have developed a rat model of postoperative pain characterized by decreased withdrawal thresholds to punctate mechanical stimuli after plantar incision. The present studies examined the response characteristics of dorsal horn neurons receiving input from the plantar aspect of the foot before and after a plantar incision placed adjacent to the low threshold area of the receptive field (RF). METHODS: Individual dorsal horn neurons from the lumbar enlargement were antidromically identified and characterized as low threshold, wide dynamic range (WDR), and high threshold (HT) based on their responses to brush and pinch. Thresholds (in millinewtons), the pinch RF, and stimulus-response functions (SRFs) to von Frey filaments characterized the neurons. SRFs were analyzed using area under the curve. Changes in background activity, punctate mechanical thresholds, SRFs, and RF were recorded after an incision was made adjacent to the most sensitive area of the RF. RESULTS: In all cells, an incision increased background activity; this remained elevated in 3 of 9 HT and 16 of 28 WDR neurons 1 h later. The SRFs were enhanced in 10 of 27 WDR neurons and in 2 of 8 HT cells after incision. Only the WDR neurons were responsive to filaments that produced withdrawal responses after incision in behavioral experiments. Increases in the RFs outside of the injured area occurred after incision in 15 of 29 WDR and 2 of 9 HT cells. CONCLUSION: A plantar incision caused dorsal horn cell activation and central sensitization. Because the threshold of HT neurons did not decrease to the range of the withdrawal responses in behavioral experiments, particular WDR dorsal horn neurons likely contribute to the reduced withdrawal threshold observed in behavioral experiments. Both WDR and HT neurons are capable of transmitting enhanced responses to strong punctate mechanical stimuli after incision.

Animals↗
PubMed1999

Primary and secondary hyperalgesia in a rat model for human postoperative pain.

BACKGROUND: Previously, the authors developed and characterized a rat model for postoperative pain to learn more about pain produced by incisions. In this study, the responses to heat and mechanical stimuli were evaluated directly on or adjacent to the incision and at varying distances from the incision. METHODS: Rats were anesthetized with halothane and incisions were made at different locations in the plantar aspect of the foot. The response frequency to a blunt mechanical stimulus, the withdrawal threshold to von Frey filaments (15-522 mN), and the withdrawal latency to radiant heat were measured. Rats were tested before surgery, 2 h later, and then daily through postoperative day 9. RESULTS: After plantar incision, persistent hyperalgesia was observed immediately adjacent to or directly on the incision to punctate and blunt mechanical stimuli, respectively. The withdrawal threshold to punctate stimuli applied 1 cm from the incision was decreased through postoperative day 1. In a transitional area, between the distant and adjacent sites, the withdrawal threshold was intermediate and the duration of hyperalgesia was transient. Heat hyperalgesia was persistent but present when the stimulus was applied to the site of injury but not to a distant site. CONCLUSION: Robust primary hyperalgesia to punctate and blunt mechanical stimuli was present. Hyperalgesia distant to the wound, or secondary hyperalgesia, occurred in response to punctate mechanical stimuli, was short-lived, and required greater forces. These results suggest that the most persistent pain behaviors in this model are largely primary hyperalgesia.

Anesthetics, Inhalation↗
PubMed1999

Incision-induced changes in receptive field properties of rat dorsal horn neurons.

BACKGROUND: To learn more about pain mechanisms produced by surgery, responses of wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons were studied before and after an incision. For this study, an incision was made in a mechanically insensitive area of the receptive field (RF) of the dorsal horn neuron in the plantar aspect of the foot and changes in mechanical response properties were studied. METHODS: Action potentials from single dorsal horn neurons were recorded in halothane anesthetized rats and these neurons were characterized as WDR or HT. Changes in background activity and responses to a variety of mechanical stimuli adjacent to the incision, distant to the injury, and in areas throughout the hindquarters were recorded. RESULTS: Fifty neurons were recorded (29 WDR, 21 HT cells); only nine of these had a sustained increase in background activity after incision. Marked decreases in threshold to von Frey filaments applied adjacent to the wound occurred in 9 of 28 WDR neurons but in none of 21 HT cells. Von Frey filament thresholds distant to the incision were largely not changed. A blunt mechanical stimulus activated 18 of 22 WDR neurons when applied directly on the incision. HT cells were largely not excited by this mechanical stimulus after incision. The RF to pinch was enlarged in 31 neurons to include areas outside the injury. Pinch RFs of both WDR and HT cells expanded. CONCLUSION: These results suggest that incisions in mechanically insensitive areas of the RF of dorsal horn neurons produced little change in background activity; expansion of pinch RFs outside the injury was common. Changing a mechanically insensitive area of the RF of WDR neurons to a mechanically sensitive area by an incision could contribute to pain behaviors that indicate primary mechanical hyperalgesia in behavioral studies.

Animals↗
PubMed1998

Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.

The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT1A receptor-mutant mice. These animals lack functional 5-HT1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT1A receptor-null mutant mice have potential as a model for investigating mechanisms through which serotonergic systems modulate affective state and mediate the actions of psychiatric drugs.

Animals↗
PubMed1998

Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain.

Evidence indicates that excitatory amino acids (EAAs) like glutamate and aspartate are important in the processing of nociceptive information in the dorsal horn of the spinal cord. Recently, the role of particular EAA receptors in pain transmission and facilitated pain states has been examined utilizing spinal administration of specific receptor antagonists. Most investigators have studied the involvement of N-methyl-D-aspartate (NMDA) EAA receptors in hyperalgesia and nociception; less is known about the importance of non-NMDA EAA receptors in animal models of persistent pain. To study the role of spinal non-NMDA EAA receptors in pain behaviors caused by an incision, we examined the effect of i.t. administered non-NMDA EAA receptor antagonists in a rat model of postoperative pain. Rats with i.t. catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound using von Frey filaments, response frequency to application of a non-punctate stimulus applied directly to the wound and non-evoked pain behaviors were measured before and after administration of i.t. 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX), or vehicle. A separate group of animals were also tested for motor impairment caused by these drugs. In the vehicle-treated group, the median withdrawal threshold for punctate hyperalgesia decreased from 522 mN before surgery to 39 mN 2 h later; hyperalgesia was persistent. Intrathecal administration of 5 or 10 nmol of NBQX returned the withdrawal threshold toward preincision values; the median withdrawal thresholds were 158 and 360 mN, respectively. Intrathecal administration of 10 nmol of DNQX similarly increased the withdrawal threshold after incision. In separate groups of animals, i.t. administration of 5 or 10 nmol of NBQX decreased the response frequency to a non-punctate stimulus applied directly to the incision from 100+/-0% 2 h after surgery to 22+/-11 and 0+/-0% 30 min after drug injection, respectively. Similar results were observed with i.t. administration of 10 nmol of DNQX. Intrathecal NBQX also inhibited non-evoked pain behavior. In conclusion, non-NMDA receptor antagonists produced a marked decrease in pain behaviors in this model of postoperative pain. Thus, non-NMDA receptors are important for the maintenance of short-term pain behaviors caused by an incision and drugs blocking these receptors may be useful for the treatment of postoperative pain in patients.

Animals↗
PubMed1998

Lack of effect of intrathecally administered N-methyl-D-aspartate receptor antagonists in a rat model for postoperative pain.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

2-Amino-5-phosphonovalerate↗
PubMed1998

Intrathecal metabotropic glutamate receptor antagonists do not decrease mechanical hyperalgesia in a rat model of postoperative pain.

UNLABELLED: Spinal metabotropic glutamate receptors (mGluR) have been implicated in hyperalgesia after injury. The purpose of this study was to examine the effects of intrathecal (IT) mGluR antagonists on mechanical hyperalgesia in a rat model of human postoperative pain. The hindpaw withdrawal threshold to punctate stimulation using von Frey filaments and the response frequency to a nonpunctate stimulus applied directly to the wound were also measured. The effects of 1T (+)-alpha-methyl-carboxyphenylglycine ([+]-MCPG), (S)-carboxyphenylglycine ([S]-4-CPG), (RS)-alphacyclopropyl-4-phosphonophenylglycine ([RS]-CPPG) and L-2-amino-3-phosphonopropionic acid (L-AP3) on incision-induced mechanical hyperalgesia were examined. The withdrawal thresholds to punctate stimuli were not different from vehicle treatment after the IT administration of (+)-MCPG (100, 500 nmol), (S)4CPG (30, 100 nmol), (RS)-CPPG (100, 500 nmol), or L-AP3 (1, 30, 100 nmol). None of the IT mGluR antagonists decreased the response frequency to the nonpunctate stimulus. The largest dose of (+)-MCPG produced sufficient receptor antagonism because spontaneous nociceptive behaviors caused by the IT administration of a mGluR agonist were reduced. IMPLICATIONS: Spinal metabotropic glutamate receptors antagonists, antinociceptive in some models of persistent pain, are not necessary for the maintenance of mechanical hyperalgesia in this rat model, which suggests that blockade of spinal metabotropic glutamate receptors may not be useful for the treatment of pain after surgery.

Animals↗
PubMed1997

Sound-induced seizures in serotonin 5-HT2c receptor mutant mice.

The epilepsies are a heterogeneous collection of seizure disorders with a lifetime expectancy risk rate of 2-4%. A convergence of evidence indicates that heritable factors contribute significantly to seizure susceptibility. Genetically epilepsy-prone rodent strains have been frequently used to examine the effect of genetic factors on seizure susceptibility. The most extensively studied of these have been strains that are susceptible to sound-induced convulsions (audiogenic seizures, or AGSs). Early observations of the AGS phenomenon were made in the laboratory of Dr. Ivan Pavlov; in the course of appetite-conditioning experiments in mice, the loud bell used to signal food presentation unexpectedly produced seizures in some animals. In 1947, DBA/2 (D2) mice were found to exhibit a genetic susceptibility to AGSs stimulated by a doorbell mounted in an iron tub. Since this discovery, AGSs have been among the most intensively studied phenotypes in behavioural genetics. Although several genetic loci confer susceptibility to AGSs, the corresponding genes have not been cloned. We report that null mutant mice lacking serotonin 5-HT2C receptors are extremely susceptible to AGSs. The onset of susceptibility is between two and three months of age, with complete penetrance in adult animals. AGS-induced immediate early gene expression indicates that AGSs are subcortical phenomena in auditory circuits. This AGS syndrome is the first produced by a known genetic defect; it provides a robust model for the examination of serotoninergic mechanisms in epilepsy.

Acoustic Stimulation↗
PubMed1997

Effect of systemic and intrathecal morphine in a rat model of postoperative pain.

BACKGROUND: To learn more about persistent pain after an incision, a rat model for postoperative pain has been developed. To further evaluate this model, the authors examined the effect of intrathecal (IT) and subcutaneous (SC) morphine, effective for postoperative pain relief in patients, on pain behaviors immediately after surgery and 1 day after surgery. METHODS: Rats were anesthetized with halothane, and a 1-cm incision was made in the plantar aspect of the foot and closed. After recovery, the rats were placed on an elevated plastic mesh floor, and withdrawal threshold was determined using calibrated von Frey filaments (15-522 mN) applied from beneath the test cage to an area adjacent to the wound at the heel. Pain behaviors also were assessed using the response frequency to a nonpunctate mechanical stimulus and a cumulative pain score. RESULTS: Mechanical hyperalgesia and nonevoked pain behaviors were present on the day of surgery and 1 day after surgery. Administration of either SC (0.3-3.0 mg/kg) or IT (0.16-5.0 micrograms) morphine reversibly increased the withdrawal threshold. The response frequency to the nonpunctate stimulus and the nonevoked pain scores also were decreased by 3 mg/kg of SC or 5 micrograms of IT morphine. Naloxone (1 mg/kg) reversed morphine-produced hypoalgesia. CONCLUSION: This is the first study to demonstrate that mechanical hyperalgesia to a nonpunctate stimulus occurs after a surgical incision in the rat. This rat model of postoperative has several similarities to postoperative patients: mechanical hyperalgesia to punctate and nonpunctate stimuli, nonevoked pain, and pain behaviors inhibited by SC and IT morphine. This model also may be useful for predicting analgesia by investigational agents for postoperative pain.

Analgesics, Opioid↗
PubMed1997

Comparison of pre- versus post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model of postoperative pain.

BACKGROUND: Preclinical studies in experimental animals suggest that preemptive analgesia may improve postoperative pain management. The beneficial effects of preemptive analgesia appear less remarkable clinically. The purpose of this study is to examine the effect of pre- and post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model for postoperative pain. METHODS: Rats with intrathecal catheters were anesthetized with halothane, and the surgical field was prepared. A saline vehicle or the test drug was administered 15 min before an incision was made in the plantar aspect of the hindpaw or after the incision was completed. After recovery, mechanical hyperalgesia to punctate and nonpunctate stimuli was measured. Rats were tested on the day of surgery for the first 5 h and each day for 6 days. RESULTS: In saline vehicle-treated rats, the median withdrawal threshold decreased from 522 mN to 54 mN or less, and the response frequency to pressure from application of the plastic disc increased from 0 +/- 0% to 96 +/- 12% or greater after incision. Hyperalgesia was persistent through 2 days after surgery and then gradually returned toward preincision values over the next 4 days. Pre- or postincision administration of either intrathecal morphine or intrathecal bupivacaine reduced hyperalgesia on the day of surgery; at all subsequent times, there were no differences between the saline vehicle groups and the drug treatment groups. There were never any significant differences between pre- and postincision treatments. CONCLUSIONS: Early reduction in pain behaviors either by pre- or postincision management had no impact on subsequent measures of hyperalgesia in this model. These results agree with a number of clinical studies and suggest that incisional pain may be initiated and maintained differently than pain in other models.

Analgesics, Opioid↗