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Biomedical subjects

G J Bennett

Publications and source records attributed to G J Bennett.

At least 37 records · Page 2Linked to original sources
PubMed1998

Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects.

UNLABELLED: Combinations of opioids and N-methyl-D-aspartate (NMDA) antagonists enhance acute antinociception and reduce opioid tolerance in some animal experiments but have received little rigorous study in humans. To quantitatively assess the nature of the interaction of these two classes of drugs in producing analgesia and cognitive impairment, we compared i.v. infusions of ketamine, alfentanil, and ketamine-alfentanil combinations in 12 normal volunteers after an intradermal injection of capsaicin. Drug doses for a 70-kg subject in this six-session, randomized, double-blind, cross-over study were: ketamine 20 mg, ketamine 5 mg, alfentanil 2 mg, alfentanil 0.5 mg, ketamine 10 mg + alfentanil 1 mg, and ketamine 2.5 mg + alfentanil 0.25 mg, given over 35 min. Outcome measures were background pain, area and magnitude of hyperalgesia to pinprick, and cognitive performance on the Digit Symbol Substitution Test and the Perception Speed Test. The results demonstrated simple additivity for the effects of ketamine and alfentanil on pain, pinprick hyperalgesia, and cognitive impairment. We conclude that, at least in this experimental pain model, there is no clear advantage or disadvantage of a ketamine-alfentanil combination over equianalgesic doses of either component. IMPLICATIONS: In a double-blind, controlled trial, we administered doses of an opioid analgesic (alfentanil), an N-methyl-D-aspartate receptor antagonist (ketamine), or their combination to normal volunteers and found no advantage of the combination over a larger dose of either drug alone in relieving pain caused by painful chemical stimulation.

Adult↗
PubMed1998

Global cerebral blood flow decreases during pain.

Positron emission tomography studies have identified a common set of brain regions activated by pain. No studies, however, have quantitatively examined pain-induced CBF changes. To better characterize CBF during pain, 14 subjects received positron emission tomography scans during rest, during capsaicin-evoked pain (250 micrograms, intradermal injection), and during innocuous vibration. Using the H215O intravenous bolus method with arterial blood sampling, global CBF changes were assessed quantitatively. Painful stimulation produced a 22.8% decrease in global CBF from resting levels (P < 0.0005). This decrease was not accounted for by arterial PCO2 or heart rate changes. Although the exact mechanism remains to be determined, this pain-induced global decrease represents a previously unidentified response of CBF.

Adult↗
PubMed1997

An experimental study of lumbar destabilization. Restabilization and bone density.

STUDY DESIGN: An investigation of the effects of bone density on lumbar spine stability using destabilizing and restabilizing procedures. OBJECTIVES: To measure cadaveric vertebral bone densities computed tomographic scans and to correlate the measured densities with lumbar spine stability in the intact and during sequential destabilization and restabilization. SUMMARY OF BACKGROUND DATA: The stabilizing effects of lumbar pedicle screw fixation have been widely described. Numerous construct failure mechanisms have been observed, including screw loosening in osteoporosis. Although previous studies have analyzed the effect of bone density on the compression strength of bone similar to that used in interbody fusion and the relationship of pedicle screw pull-out strength to vertebral bone density, a combined study of bone density and construct stability using an interbody bone spacer with pedicle fixation has not been performed. METHODS: Bone densities were measured in 20 human cadaveric lumbar spines using computed tomography scans and a hydroxyapatite phantom. After the specimens were mounted in a testing frame, the L4-L5 motion segments were subjected to cyclic axial compression-torsional loads, and axial and rotational intervertebral displacements were monitored. Laminectomy, facetectomy, and pedicle screw-plate fixation were performed sequentially in three specimens. Ten others underwent these procedures with an additional destabilization procedure, discectomy, after facetectomy. Seven others underwent the same sequence as the previous group, followed by the insertion of interbody bone. Cyclic testing was resumed after each procedure. RESULTS: Average bone densities varied widely among the specimens. Average bone densities of the pedicle and of the vertebral body for individual specimens were well-correlated (r = 0.897). Displacements were recorded as a percentage of the intact state before destabilization; average percentages are reported as follows: axial displacements increased after facetectomy (145%) and subsequent discectomy (251%), and rotational displacements increased after facetectomy (295%) and discectomy (390%). Instrumentation without interbody bone resulted in specimens with decreased axial (126%) and rotational (156%) displacements. The addition of interbody bone further decreased axial (111%) and rotational (117%) displacements. The rotational stabilization provided by instrumentation was well-correlated with vertebral bone density (r = 0.804). This correlation was enhanced by the use of interbody bone (r = 0.939). CONCLUSION: The unstable lumbar spine can be partially stabilized using fixation. Interbody bone provides additional stability. The immediate stability provided by pedicle screws is greater in lumbar vertebrae with higher bone density.

Adult↗
PubMed1997

The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain.

The effects of a high affinity cannabinoid receptor agonist were evaluated in rats subjected to chronic constriction injury of the sciatic nerve (CCI) or a sham operation. Intraperitoneal (i.p.) injections of the active, but not the inactive enantiomer, alleviated the pain behavior exhibited by CCI animals in a dose dependent manner. Moreover, at doses ranging from 0.43 to 4.3 mg/kg effects on sensitivity to a heat stimulus were observed neither in the paw contralateral to the sciatic ligation, nor in animals subjected to sham surgery. Animals subjected to CCI and treated with 4.3 mg/kg exhibited hypoalgesia in the paw ipsilateral to the ligated sciatic, i.e. heat hypoalgesia was completely reversed. The hypoalgesia is presumed to be the results of unmasking of a sensory deficit reflecting the known loss of C and A delta with CCI. Although side effects were present in some CCI animals subjected to the high dose (4.3 mg/kg), a moderate dose (2.14 mg/kg) completely alleviated the thermal and mechanical hyperalgesia, and mechanical allodynia without side effects. In addition to identifying a potential drug treatment for painful neuropathy, this study suggests that changes in cannabinoid receptors occurs in nerve injured animals.

Analgesics, Non-Narcotic↗
PubMed1997

Diversity of Streptococcus agalactiae and Staphylococcus aureus ribotypes recovered from New York dairy herds.

OBJECTIVES: To develop a reference database for characterization of bovine Staphylococcus aureus and Streptococcus agalactiae strains by automated ribotyping and to use it to assess the discriminatory power of this typing procedure and the geographic distribution of Sta aureus and Str agalactiae strains in New York state dairy herds. SAMPLE POPULATION: 22 commercial dairy herds. PROCEDURE: Isolates of Sta aureus and Str agalactiae from bovine milk were identified by standard bacteriologic procedures, then typed by automated ribotyping. Antimicrobial susceptibility of isolates was tested in vitro. Two indicators made from the data were percentage of farms with multiple ribotypes and percentage of single ribotypes found in several geographic regions. Standard bacteriologic diagnosis, automated ribotyping, and determination of antibiograms (Kirby-Bauer method) also were done. RESULTS: Of 50 Sta aureus and 44 Str agalactiae isolates from composite milk samples of 12 and 10 herds, respectively, 18 and 14 ribotypes, respectively, were identified. The discriminatory power of automated ribotyping was approximately 0.96 (Hunter-Gaston's formula). A higher percentage of herds with Sta aureus had multiple ribotypes. The most common Sta aureus ribotypes tended to have broader geographic distribution. Some Sta aureus ribotypes were significantly associated with antibiotic resistance profiles. CONCLUSIONS: Automated ribotyping appears to characterize bovine strains of bacteria associated with intramammary infections with a high discriminatory index. Potential applications include identification of strains that appear to have broad geographic distribution suggesting interfarm transfer, discrimination between recurrent versus new intramammary infections (ie, for control of Str agalactiae and Sta aureus), and evaluation of antibiotic therapy.

Animals↗
PubMed1996

The sympathetic nervous system contributes to capsaicin-evoked mechanical allodynia but not pinprick hyperalgesia in humans.

The contribution of the sympathetic nervous system (SNS) to pain, mechanical allodynia (MA), and hyperalgesia in humans is controversial. A clearer understanding is crucial to guide therapeutic use of sympatholytic surgery, blocks, and drug treatments. In rats, capsaicin-evoked MA, and to some extent, pinprick hyperalgesia (PPH), can be blocked with alpha-adrenoreceptor antagonists. In this study, we examined the contribution of the SNS to MA and PPH in normal human subjects by blocking alpha-adrenoreceptors with intravenous phentolamine. In a double-blinded, placebo-controlled, crossover study, subjects were given IV saline or phentolamine, 1 mg/kg over 20 min. Ten minutes after the start of the infusion, subjects received 100 micrograms of intradermal capsaicin on the foot dorsum with the temperature of the injected site clamped at 36 degrees C. The temperature of the uninjected foot was used to monitor the degree of alpha-adrenoreceptor blockade produced by phentolamine. Ongoing pain and MA and PPH areas were measured every 5 min for 60 min. A significantly greater increase in temperature on the uninjected foot was seen during the phentolamine infusion compared with the saline infusion, indicating alpha-adrenergic blockade. Significantly less MA was observed with the phentolamine infusion 10-25 min after capsaicin injection than with the saline infusion. No significant differences in ongoing pain or PPH areas were seen between the two infusions at any time. Our results suggest that capsaicin-evoked MA and PPH have different mechanisms, with the SNS having a role in MA but not in PPH or ongoing pain.

Capsaicin↗
PubMed1996

Vanilloid receptor loss is independent of the messenger plasticity that follows systemic resiniferatoxin administration.

Resiniferatoxin (RTX) depletes vanilloid (capsaicin) receptors from lumbar dorsal root ganglia (DRG) of the rat. In addition, RTX causes changes in neuropeptide and nitric oxide synthase expression in lumbar DRG neurons, similar to those described following axotomy; this latter phenomenon is referred to as messenger plasticity. These findings suggested that vanilloid receptor loss may be part of the plasticity that follows RTX treatment. Here we show that vanilloid receptor expression, as detected by [3H]RTX autoradiography, is not changed in lumbar DRGs of axotomized rats, nor is it altered in a rat model (chronic constriction injury) of neuropathic pain. Thus, the in vivo expression of vanilloid receptors detected by specific [3H]RTX binding does not require the presence of intraaxonally transported trophic factors such as nerve growth factor. We conclude that messenger plasticity and vanilloid receptor loss are mediated by distinct mechanisms.

Animals↗
PubMed1996

Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories. Evidence for a central mechanism.

BACKGROUND: The finding in some patients with neuropathic pain that mechanical allodynia (pain evoked by light touch) and hyperalgesia (supranormal pain evoked by painful stimuli) extend beyond the territory of a single nerve or spinal sensory root (extraterritorial pain) often prompts a diagnosis of psychiatric illness. The hypothesis that focal nociceptive input in a single nerve territory can result in allodynia and hyperalgesia in a nerve territory adjacent to the input was investigated in normal human subjects. METHODS: On separate days, 13 healthy volunteers each received left radial and ulnar nerve blocks. After block of either nerve, sensation remaining for three classes of afferents (A beta low-threshold mechanoreceptors, A delta nociceptors, and C polymodal nociceptors) allowed inference of the nerve territory of the adjacent nerve, and the area of overlapping innervation. On a third day, 1,000 micrograms intradermal capsaicin was administered into a site such that C-nociceptor input was confined to the ulnar nerve territory. Areas of brush allodynia and pinprick hyperalgesia were determined. RESULTS: Spread of brush allodynia beyond all three borders of the ulnar nerve territory occurred in 9 of 13 patients (for these subjects, range 5-28 mm), whereas spread of pinprick hyperalgesia beyond all borders of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). Spread of brush allodynia beyond the A beta border of the ulnar nerve territory occurred in 10 of 13 subjects (range 4-35 mm); and spread of pinprick hyperalgesia beyond the A delta border of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). CONCLUSIONS: It is concluded that activation of C-nociceptors evokes a state of central sensitization that may manifest itself by the appearance of extraterritorial pain abnormalities.

Adult↗
PubMed1996

Efficacy of florfenicol for treatment of clinical and subclinical bovine mastitis.

OBJECTIVE: To evaluate efficacy of florfenicol treatment for bovine mastitis caused by Streptococcus agalactiae, Staphylococcus aureus nonagalactiae streptococci, coagulase-negative staphylococci, Escherichia coli, Klebsiella sp, and others. DESIGN: Double blind study with cases randomly assigned to 1 of 2 treatment groups. SAMPLE POPULATION: 861 cows/10 commercial dairy farms. PROCEDURE: Experimental (750 mg of florfenicol) or control (200 mg of cloxacillin) treatment was administered by intramammary infusion every 12 hours for 3 treatment to all cases. Treatments were randomly assigned identified only by numerical labels. To retain blinding, the longer withdrawal time was adhered to for all cases. Cases remained in the study only if there was no other treatment. Quarter samples were recultured 14, 21, and 28 days later. If all samples after day 1 were culture negative, the case was defined as cured. If only 1 of the follow-up results was positive, the case was considered cured if the day-28 somatic cell count was < 300,000/ ml. Failure of treatment was defined as 2 or more culture positive follow-up samples. RESULTS: Florfenicol and cloxacillin did not differ significantly in efficacy versus clinical (n = 85) or subclinical (n = 71) bovine mastitis, or for any etiologic agent (X2). Overall cure rates for mastitis were: Str agalactiae, 5 of 8 (63%); Sta aureus, 5 of 54 (9%); Streptococcus sp, 16 of 35 (46%); Staphylococcus sp, 7 of 33 (21%); E coli, 5 of 11 (46%); Klebsiella sp, 3 of 6 (50%); others, 1 of 9 (11%); and all cases, 42 of 156 (27%). CONCLUSIONS: Florfenicol did not offer any advantage over cloxacillin in efficacy against bovine mastitis. Overall cure rates were low. As with most mastitis treatment regimens poor efficacy may be partly attributable to the short duration of treatment.

Animals↗
PubMed1995

Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo.

NMDA antagonists and opioids relieve experimentally produced hyperalgesia in animals and humans, presumably by attenuating a heightened central nervous system response to afferent input. A few small studies in patients have suggested that intravenous boluses or rapid infusions of the N-methyl-D-aspartate (NMDA) antagonist ketamine relieve some neuropathic pains but also produce disturbances of cognition and mood. In a randomized, double-blind, crossover trial, we treated eight patients with chronic posttraumatic pain and widespread mechanical allodynia with 2-h intravenous infusions of the NMDA antagonist ketamine (mean dose, 58 mg), the opioid mu-receptor agonist alfentanil (mean dose, 11 mg), and placebo. The patients were selected because extensive sensory testing suggested that altered central processing contributed to their symptoms. The slow rate of drug infusion was chosen to see if pain relief would precede dose-limiting side effects. Means of the peak effect scores achieved during the 2-h infusion were for pain relief: ketamine, 65%, alfentanil, 46%, and placebo, 22% (p < 0.01 for ketamine and p = 0.08 for alfentanil, each compared to placebo); and for relief of allodynia: ketamine, 71%, alfentanil, 57%, and placebo, 21% (p < 0.01 for both ketamine and alfentanil). Appreciable symptomatic relief developed only after the onset of unpleasant drug side effects. After the infusion was stopped, pain relief disappeared before the side effects resolved. We conclude that NMDA antagonists may have promise for the treatment of neuropathic pain, but strategies are needed to improve their therapeutic ratio, such as intrathecal administration or systemic treatment with more selective drugs.

Adult↗
PubMed1995

Felbamate relieves several abnormal pain sensations in rats with an experimental peripheral neuropathy.

The antiepileptic drug, felbamate, was tested in a rat model of painful peripheral neuropathy (the chronic constriction injury model). Intraperitoneal doses of 150, 300 and 600 mg/kg were given to animals with established heat-hyperalgesia, mechanohyperalgesia, mechano-allodynia and signs of spontaneous pain (hindpaw guarding). Postinjection tests were conducted 2, 6, 12, 24 and 48 h later. The 150 mg/kg dose had little or no effect on any measure. Significant reductions in all measures of abnormal pain were seen after the 300 and 600 mg/kg doses; relief lasted 2 to 12 h. Side effects were trivial or absent by 2 h postinjection. Felbamate's actions were generally antihyperalgesic and antiallodynic, rather than analgesic, in that the responsiveness of the control (sham-operated) hindpaw was unaffected. We conclude that felbamate suppresses neuropathic pain sensations and that its effectiveness may be due to multiple mechanisms of action. The recently discovered severe side-effect liability of felbamate is likely to preclude its clinical application.

Analgesics↗
PubMed1995

Synthetic omega-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats.

In patients and animals with painful peripheral neuropathies, spontaneous ectopic discharge from injured primary afferents is hypothesized to maintain a central state of hyperexcitability that underlies hyperalgesia and allodynia. Temporary suppression of this discharge allows the central state to normalize, such that hyperalgesia and allodynia are absent or reduced until the resumption of the discharge rekindles central hyperexcitability. Previous work suggests that Ca++ channels are involved in the genesis of spontaneous discharge from injured afferents. We applied SNX-111 and SNX-124 (0.1-3.0 micrograms), synthetic homologs of omega-conopeptides (MVIIA and GVIA, respectively) and potent blockers of neuronal N-type voltage-sensitive Ca++ channels, to the site of nerve injury via chronically implanted perineural cannulae in rats with an experimental painful peripheral neuropathy (the chronic constriction injury model). Heat-hyperalgesia and mechano-allodynia were reduced for at least 3 hr. Drug application to a normal nerve had no effect on responses to heat or mechanical stimuli. These results suggest that N-type Ca++ channel blockers may be useful in the treatment of the abnormal pains that occur after nerve injury.

Animals↗
PubMed1994

Magnesium suppresses neuropathic pain responses in rats via a spinal site of action.

We tested the ability of Mg2+ therapy to block the heat-hyperalgesia, mechano-allodynia and mechano-hyperalgesia that are seen in rats with an experimental painful peripheral neuropathy (the CCI model of Bennett and Xie). Systemic Mg2+ (magnesium sulfate, 600 mg/kg, s.c.) significantly reduced heat-hyperalgesia and mechano-allodynia for 2-24 h post-injection, but had no effect on mechano-hyperalgesia. Intrathecal (i.t.) injections of Mg2+ (185-750 micrograms) at the level of the lumbar spinal cord significantly reduced heat-hyperalgesia, but perineural application (750 and 7,000 micrograms) to the site of nerve injury had no effect. Neither s.c. nor i.t. Mg2+ had any effect on the responses from the control, sham-operated side. We conclude that Mg2+ has a spinal site of action. Mg2+ therapy may be of limited use in the treatment of human painful peripheral neuropathy.

Animals↗
PubMed1994

Neuropathic pain sensations are differentially sensitive to dextrorphan.

Rats with an experimental painful peripheral neuropathy (the CCI model) display heat-hyperalgesia and mechanoallodynia. Previous work has shown that the heat-hyperalgesia is suppressed by dextrorphan (DEX) and other N-methyl-D-aspartate (NMDA) receptor antagonists. The present work shows that when tested in the same rats, a dose of DEX that is maximally effective against heat-hyperalgesia has no effect on mechano-allodynia. The results suggest that different kinds of abnormal pain sensations may be caused by different pathophysiologic mechanisms that may respond differently to drug therapy.

Animals↗
PubMed1993

Does pain damage spinal cord neurons? Transsynaptic degeneration in rat following a surgical incision.

In prior studies, rats with a chronic constriction injury to the sciatic nerve have been found to have small- to medium-sized, pyknotic, and hyperchromatic neurons ('dark neurons'; DNs) in spinal dorsal horn laminae I-III. It has been proposed that DNs are produced by an excitotoxic insult involving N-methyl-D-aspartate receptor activation subsequent to ectopic nociceptor discharge, and that at least some DNs are inhibitory interneurons whose functional impairment or death contributes to a central state of hyperexcitability that underlies neuropathic hyperalgesia and allodynia. We show here that laminae I-III DNs are also present 2 days after a surgical procedure that does not include major nerve damage. We propose that this is also the result of a nociceptor-driven excitotoxic insult and that the functional impairment of the affected neurons may contribute to postoperative pain and tenderness.

Animals↗
PubMed1993

Dextrorphan relieves neuropathic heat-evoked hyperalgesia in the rat.

Dextrorphan (DEX), a non-competitive NMDA receptor antagonist, was given intraperitoneally and intrathecally (i.t.) to rats with an experimental painful peripheral mononeuropathy. The neuropathy was created by placing loosely constrictive ligatures around the sciatic nerve, and the pain threshold was studied with the paw-flick method. The effects of DEX on the neuropathic heat-evoked hyperalgesia that follows this nerve injury were determined during the period of peak symptom severity. DEX given i.p. relieved heat-evoked hyperalgesia in a dose-dependent manner without producing motor impairment. The highest doses tested (12.5 and 25 mg/kg) produced a large but incomplete block (about 50%). DEX had no effect on the responsiveness of the paw on the control side. i.t. injection of 20 micrograms DEX completely blocked heat-hyperalgesia when tested 1 h later; again, the effect was achieved without motor impairment and without any change on the control side. These results suggest that DEX may be useful in the treatment of human neuropathic pain.

Animals↗
PubMed1993

An animal model of neuropathic pain: a review.

Recent work has succeeded in producing models of painful peripheral neuropathies in laboratory animals. There is evidence that the animals experience both abnormal spontaneous pain and abnormal evoked pains (allodynia and hyperalgesia). Experimental analyses of these models have demonstrated potential pathophysiologic mechanisms in both the peripheral and central nervous systems; it is likely that the model neuropathic pain syndromes are due to several different mechanisms. One line of evidence suggests that these pain states gradually become centralized due to an excitotoxic effect on spinal cord dorsal horn inhibitory interneurons. The role of the sympathetic nervous system appears to vary, depending on the type of nerve injury and the temporal evolution of the syndrome. There is evidence indicating that the abnormality of cutaneous temperature regulation that often accompanies painful peripheral neuropathy is not necessarily due to the activity of sympathetic vasomotor efferents.

Animals↗