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Biomedical subjects

M S Gold

Publications and source records attributed to M S Gold.

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

A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat.

We report evidence for a contribution of tetrodotoxin-resistant sodium current (TTX-R INa) to prostaglandin E2 (PGE2)-induced hyperalgesia. Behavioral experiments were performed in rats chronically implanted with spinal cannulae. The study employed intrathecal administration of oligodeoxynucleotide (ODN) antisense to the recently cloned channel underlying TTX-R INa (PN3/SNS). The nociceptive flexion reflex was employed to determine changes in mechanical stimulus-induced paw-withdrawal threshold. Administration of antisense but not of sense or mismatch ODN, led to a decrease in PGE2-induced hyperalgesia. PGE2-induced hyperalgesia returned to normal 7 days after the last injection of antisense ODN. Antisense ODN selectively and significantly reduced TTX-R INa current density in cultured sensory neurons. Our observations support the hypothesis that modulation of TTX-R INa, present in peripheral terminals of primary afferent nociceptors, contributes, at least in part, to inflammatory hyperalgesia. Since TTX-R INa is found only in primary afferent nociceptors, our findings suggest TTX-R INa as a promising target for novel therapeutic interventions for the treatment of inflammatory pain.

Animals↗
PubMed1998

Immobility and flight associated with antinociception produced by activation of the ventral and lateral/dorsal regions of the rat periaqueductal gray.

It has long been known that the periaqueductal gray (PAG) plays an important role in the modulation of nociception. Given that activation of the lateral PAG also produces wild running and tachycardia, it has been suggested that PAG mediated antinociception is part of an integrated defensive reaction. However, an alternative hypothesis is that these effects are merely a secondary response to aversive brain stimulation. If antinociception and flight reactions are caused by aversive brain stimulation, then these effects should always occur together. The objective of the present study was to determine whether antinociception and locomotion could be dissociated by microinjecting morphine and kainic acid into various subdivisions of the caudal PAG. Non-selective activation of lateral and dorsal regions of the PAG by microinjection of kainic acid produced wild running, while injections into the ventrolateral PAG produced immobility. Microinjection of morphine evoked similar locomotor effects, although the onset to effect was slower with morphine (approximately 5 min vs. 1 min for kainic acid), and the antinociceptive efficacy of microinjecting 0.2 microl of morphine was less than with kainic acid injections. In fact, microinjection of morphine evoked locomotor effects in the absence of antinociception on 39% of the tests. Increasing the injection volume to 0.4 microl (dose remained at 5 microg) greatly enhanced the likelihood that antinociception and locomotor effects (e.g. running, freezing, circling) occurred simultaneously (79%). These findings indicate that, although distinct locomotor effects are associated with antinociception from the ventral and more dorsal regions of the PAG, antinociceptive and locomotor effects can occur independently. This finding is consistent with the hypothesis that ventral and dorsal regions of the PAG integrate defensive freezing and flight reactions, respectively.

Animals↗
PubMed1998

Multiple neurological abnormalities in mice deficient in the G protein Go.

The G protein Go is highly expressed in neurons and mediates effects of a group of rhodopsin-like receptors that includes the opioid, alpha2-adrenergic, M2 muscarinic, and somatostatin receptors. In vitro, Go is also activated by growth cone-associated protein of Mr 43,000 (GAP43) and the Alzheimer amyloid precursor protein, but it is not known whether this occurs in intact cells. To learn about the roles that Go may play in intact cells and whole body homeostasis, we disrupted the gene encoding the alpha subunits of Go in embryonic stem cells and derived Go-deficient mice. Mice with a disrupted alphao gene (alphao-/- mice) lived but had an average half-life of only about 7 weeks. No Goalpha was detectable in homogenates of alphao-/- mice by ADP-ribosylation with pertussis toxin. At the cellular level, inhibition of cardiac adenylyl cyclase by carbachol (50-55% at saturation) was unaffected, but inhibition of Ca2+ channel currents by opioid receptor agonist in dorsal root ganglion cells was decreased by 30%, and in 25% of the alphao-/- cells examined, the Ca2+ channel was activated at voltages that were 13.3 +/- 1.7 mV lower than in their counterparts. Loss of alphao was not accompanied by appearance of significant amounts of active free betagamma dimers (prepulse test). At the level of the living animal, Go-deficient mice are hyperalgesic (hot-plate test) and display a severe motor control impairment (falling from rotarods and 1-inch wide beams). In spite of this deficiency, alphao-/- mice are hyperactive and exhibit a turning behavior that has them running in circles for hours on end, both in cages and in open-field tests. Except for one, all alphao-/- mice turned only counterclockwise. These findings indicate that Go plays a major role in motor control, in motor behavior, and in pain perception and also predict involvement of Go in Ca2+ channel regulation by an unknown mechanism.

Abnormalities, Multiple↗
PubMed1998

Comorbid cigarette and alcohol addiction: epidemiology and treatment.

The close association of nicotine addiction and alcoholism is well established. As many as 80% of alcoholics smoke, and 30% of smokers are alcoholics. The mortality from cigarette smoking and alcoholism individually is very high, as an estimated 400,000 deaths from tobacco and 100,000 deaths from alcoholism are reported annually. Cigarettes and alcohol interact to cause certain cancers, e.g., head and neck. Only recently has attention been focused on the role of tobacco in abstinent alcoholics. An important study found high rates of mortality from tobacco in abstinent alcoholics in recovery. However, the mortality rates from alcoholism were high and predominant. Of great importance is that studies show that abstinence from alcohol essentially eliminates the premature deaths or increased mortality rates from active alcoholism. Similar studies showing a reduction in mortality from abstinence in nicotine addiction have not been forthcoming. The importance of treating nicotine addiction, however, is clear to reduce the high mortality rates from tobacco smoking in active or abstinent alcoholics.

Comorbidity↗
PubMed1998

Lidocaine toxicity in primary afferent neurons from the rat.

Evidence from both clinical studies and animal models suggests that the local anesthetic, lidocaine, is neurotoxic. However, the mechanism of lidocaine-induced toxicity is unknown. To test the hypothesis that toxicity results from a direct action of lidocaine on sensory neurons we performed in vitro histological, electrophysiological and fluorometrical experiments on isolated dorsal root ganglion (DRG) neurons from the adult rat. We observed lidocaine-induced neuronal death after a 4-min exposure of DRG neurons to lidocaine concentrations as low as 30 mM. Consistent with an excitotoxic mechanism of neurotoxicity, lidocaine depolarized DRG neurons at concentrations that induced cell death (EC50 = 14 mM). This depolarization occurred even though voltage-gated sodium currents and action potentials were blocked effectively at much lower concentrations. (EC50 values for lidocaine-induced block of tetrodotoxin-sensitive and -resistant voltage-gated sodium currents were 41 and 101 microM, respectively.) At concentrations similar to those that induced neurotoxicity and depolarization, lidocaine also induced an increase in the concentration of intracellular Ca++ ions ([Ca++]i; EC50 = 21 mM) via Ca++ influx through the plasma membrane as well as release of Ca++ from intracellular stores. Finally, lidocaine-induced neurotoxicity was attenuated significantly when lidocaine was applied in the presence of nominally Ca(++)-free bath solution to DRG neurons preloaded with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Our results indicate: 1) that lidocaine is neurotoxic to sensory neurons; 2) that toxicity results from a direct action on sensory neurons; and 3) that a lidocaine-induced increase in intracellular Ca++ is a mechanism of lidocaine-induced neuronal toxicity.

Action Potentials↗
PubMed1998

Management of withdrawal syndromes and relapse prevention in drug and alcohol dependence.

The primary care physician is in a good position to diagnose, manage and intervene with patients who are undergoing the process of treatment and recovery from alcohol and drug disorders. Medications such as benzodiazepines are effective in the treatment of withdrawal syndromes, and naltrexone and disulfiram can be used to augment relapse prevention. Patients may also participate in psychosocial methods of addiction treatment that can reduce the risk of relapse and improve their psychosocial, health, legal and employment status.

Alcoholism↗
PubMed1997

Alpha 2-adrenergic receptor subtypes in rat dorsal root and superior cervical ganglion neurons.

To determine which alpha 2-adrenergic receptor subtypes are present in primary afferent and sympathetic postganglionic neurons we have performed in situ hybridization and immunohistochemistry experiments on rat dorsal root and superior cervical ganglia. Reverse transcriptase polymerase chain reaction was used as a preliminary screen for the presence of mRNA encoding alpha 2-adrenergic subtypes in dorsal root and superior cervical ganglia; polymerase chain reaction primers amplified distinct regions of the rat alpha 2A-(RG20), alpha 2B-(RNG) and alpha 2C-(RG10) adrenergic receptor subtypes in mRNA extracted from lumbar dorsal root and superior cervical ganglia. To localize receptors to cell types in the ganglia, in situ hybridization was performed on cryosections of dorsal root and superior cervical ganglia with oligonucleotide probes designed to distinguish between mRNA encoding for alpha 2-adrenergic receptor subtypes. Immunohistochemistry was performed with a polyclonal antibody against the alpha 2A-adrenergic receptor subtype. Our results with reverse transcriptase polymerase chain reaction indicate that all three alpha 2-adrenergic receptor subtypes are expressed in dorsal root and superior cervical ganglia. Data from the in situ hybridization experiments indicated that the mRNA detected with the reverse transcriptase polymerase chain reaction was present in neuronal cell bodies, except for the mRNA encoding the alpha 2A-adrenergic receptor which was not detectable in dorsal root ganglia. The distribution of mRNA encoding alpha 2B- and alpha 2C-adrenergic receptor subtypes among dorsal root ganglion neurons and alpha 2A-, alpha 2B- and alpha 2C-adrenergic receptor subtypes among superior cervical ganglion neurons suggests that multiple adrenergic receptor subtypes are present in a single neuron. Neuronal cell bodies in both the dorsal root and superior cervical ganglion consistently demonstrated alpha 2A-adrenergic receptor-like immunoreactivity. The apparent co-expression of multiple alpha 2-adrenergic receptor subtypes in dorsal root and superior cervical ganglion neurons enables a single transmitter to produce a number of effects in the same neuron; which receptors are functionally active may vary with the presence of nerve injury, inflammation or other physiological and pathophysiological conditions.

Animals↗
PubMed1997

Comparison of lumbar and thoracic epidural narcotics for postoperative analgesia in patients undergoing abdominal aortic aneurysm repair.

OBJECTIVE: To determine whether there is an advantage of thoracic over lumbar epidural narcotics for postoperative analgesia in patients undergoing abdominal aortic aneurysm repair. DESIGN: A prospective randomized study. SETTING: Subjects were inpatients at an academic medical center. PARTICIPANTS: Fifty-two patients scheduled for elective abdominal aortic aneurysm repair. INTERVENTIONS: Subjects were randomly assigned to receive lumbar or thoracic epidural narcotics. Group 1 (n = 26) had lumbar, and group 2 (n = 26) had thoracic epidural catheters placed preoperatively. All patients were monitored with pulmonary artery catheters and arterial catheters, and had general endotracheal anesthesia, in addition to epidural anesthesia with 2% lidocaine. All patients received 5 mg of epidural morphine after intubation. Pain scores were monitored hourly for 36 hours using a visual analog scale, and additional narcotics were given, depending on the level of pain. Complications caused by epidural narcotics were recorded. RESULTS: There was no difference between groups as to the daily dose of narcotics or the time between narcotic doses. Hourly pain scores showed significant differences during hours 6, 7, 8, 20, 34, and 36, with pain scores being lower in group 1. There was no difference in the rate of complications between the groups. CONCLUSION: There is no advantage of thoracic over lumbar epidural analgesia using morphine in patients undergoing abdominal aortic aneurysm repair.

Aged↗
PubMed1997

Preschool hearing screening: evaluation of a parental questionnaire.

OBJECTIVE: To evaluate the validity of a parental questionnaire used to screen preschool children for persistent hearing impairment. METHODOLOGY: Six-hundred and eighty-five children aged 4-5 years from a Metropolitan area of Adelaide, Australia, were enrolled. Each parent completed a questionnaire aimed at detecting parental concerns about hearing impairment. Screening audiometry was then performed. Children who failed the initial audiometry screening underwent repeat audiometry screening 6-8 weeks later. The audiometry and questionnaire data were then compared. RESULTS: Of the 657 children who successfully completed initial audiometry, 544 (83%) passed and 113 (17%) failed. Of the 84 children who had follow-up audiometry, 64 (76%) passed. Parental concerns were identified on questionnaire in 50% of all children. Neither individual questions nor the number of concerns were found to relate to audiometry results. Compared with audiometry results, the hearing screening questionnaire had a sensitivity of 56% and specificity of 52%. CONCLUSIONS: The hearing questionnaire used in this study and in several Australian states is an ineffective screening test for detecting persistent hearing loss.

Audiometry↗
PubMed1996

Selective attenuation of mu-opioid receptor-mediated effects in rat sensory neurons by intrathecal administration of antisense oligodeoxynucleotides.

To test the hypothesis that the expression of specific proteins on peripheral terminals of primary afferents can be attenuated by intrathecal administration of antisense oligodeoxynucleotides (ODNs), we administered ODNs antisense to the mu-opioid receptor to male Sprague-Dawley rats via chronically implanted intrathecal cannulae. Antisense but not mismatch ODN treatment significantly decreased peripheral (D-Ala2, N-Me-Phe4, Gly5-ol)-enkephalin (DAMGO) inhibition of prostaglandin E2 (PGE2) hyperalgesia. Antisense treatment affected neither the magnitude of PGE2 hyperalgesia nor the antinociception produced by a peripherally administered adenosine A1-agonist. The antinociceptive effects of DAMGO was fully recovered 8 days after cessation of ODN treatment. DAMGO-induced inhibition of voltage-gated Ca2+ currents (VGCC), in cultured dorsal root ganglion (DRG) neurons from rats treated with ODNs, was also significantly reduced by antisense but not mismatch ODNs. Taken together, these observations suggest that intrathecal administration of antisense ODNs can be used to study the function of proteins present in the peripheral terminals of primary afferent neurons.

Analgesics↗
PubMed1996

DAMGO inhibits prostaglandin E2-induced potentiation of a TTX-resistant Na+ current in rat sensory neurons in vitro.

We have tested the hypothesis that the mu-opioid agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO), inhibits prostaglandin E2 (PGE2)-induced modulation of a tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa) in putative nociceptors in vitro. Patch-clamp electrophysiological techniques were used on cultured dorsal root ganglion neurons from the adult rat. PGE2 (1 microM) induced a 103 +/- 22.8% increase in peak TTX-R INa. The PGE2-induced increase in TTX-R INa in the presence of 1 microM DAMGO (24.9 +/- 7.7%), was significantly less than that induced by PGE2 alone. In contrast, when DAMGO was applied after PGE2, PGE2-induced increase in TTX-R INa (85.3 +/- 19.6%) was not significantly different than the increase in the current induced by PGE2 alone. Preapplication of naloxone (10 microM) blocked DAMGO-induced inhibition of the PGE2-induced increase in TTX-R INa. DAMGO, alone, had no effect on peak TTX-R INa (1.4 +/- 1.5% of baseline). Our observation that DAMGO prevents PGE2-induced potentiation of TTX-R INa is consistent with the suggestion that modulation of TTX-R INa underlies the hyperalgesic agent-induced increase in the excitability of nociceptors associated with sensitization and hyperalgesia. Furthermore, our data suggest that inhibition of hyperalgesic agent induced modulation of TTX-R INa may be a novel mechanism underlying opioid-induced antinociception.

Analgesics↗
PubMed1996

Role of a Ca(2+)-dependent slow afterhyperpolarization in prostaglandin E2-induced sensitization of cultured rat sensory neurons.

To determine if inhibition of a Ca(2+)-dependent slow afterhyperpolarization (AHPslow) contributes to prostaglandin E2 (PGE2)-induced sensitization of DRG neurons, we have used patch-clamp electrophysiological techniques on cultured dorsal root ganglion (DRG) neurons from the adult rat. In support of a role for AHPslow in sensitization of DRG neurons, we demonstrate that: (1) AHPslow expression is restricted to a subpopulation of putative nociceptors; (2) burst duration is controlled by AHPslow in these neurons; and (3) in some neurons, PGE2 decreases AHPslow and produces a concomitant increase in the number of action potentials generated in response to depolarizing current injection. However, our results also demonstrate that AHPslow modulation is not sufficient to explain PGE2-induced sensitization in the majority of DRG neurons because: (1) the size of the population of DRG neurons expressing AHPslow is less than half the size of the population of DRG neurons sensitized by PGE2; (2) PGE2 produces a decrease in action potential threshold as well as an increase in the number of action potentials in response to current injection, while inhibition of AHPslow has little effect on threshold; and (3) the sensitizing effects of PGE2 are dissociated from its effects on AHPslow in more than half of neurons tested. We conclude that PGE2-induced sensitization must involve the modulation of ionic currents in addition to that underlying AHPslow.

Animals↗
PubMed1996

Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors.

Sensitization of primary afferent neurons underlies much of the pain and tenderness associated with tissue injury and inflammation. The increase in excitability is caused by chemical agents released at the site of injury. Because recent studies suggest that an increase in voltage-gated Na+ currents may underlie increases in neuronal excitability associated with injury, we have tested the hypothesis that a tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa), selectively expressed in a subpopulation of sensory neurons with properties of nociceptors, is a target for hyperalgesic agents. Our results indicate that three agents that produce tenderness or hyperalgesia in vivo, prostaglandin E2, adenosine, and serotonin, modulate TTX-R INa. These agents increase the magnitude of the current, shift its conductance-voltage relationship in a hyperpolarized direction, and increase its rate of activation and inactivation. In contrast, thromboxane B2, a cyclooxygenase product that does not produce hyperalgesia, did not affect TTX-R INa. These results suggest that modulation of TTX-R INa is a mechanism for sensitization of mammalian nociceptors.

Adenosine↗
PubMed1996

Inhibition of unstimulated exocrine pancreatic secretion by peptide YY in the rat.

Peptide YY is an ileocolonic peptide known to inhibit postprandial and cholecystokinin-induced pancreatic exocrine secretion. It has also been shown to increase intestinal water and electrolyte absorption. These findings implicate PYY as being potentially useful for controlling watery diarrhea. Although its inhibitory effect on stimulated pancreatic secretion has been well established, PYY effects on interdigestive, unstimulated pancreatic secretion is not known. This study was designed to evaluate the effect of PYY on basal pancreatic exocrine secretion in a conscious rat. Male Sprague-Dawley rats were prepared with catheters for internal biliary bypass, pancreatic juice collection, and intraduodenal reinfusion of pancreatic juice. Jugular and carotid catheters were inserted for drug infusions and blood sampling. After overnight recovery, fasting rats were infused over 6 hours with saline or PYY (400 or 800 pmol/kg/hr). Pancreatic juice was measured and sampled at 60-minute intervals for volume and its protein and bicarbonate content. The remainder was reinfused into the duodenum. Before and after the experiment, pancreatic juice was automatically reinfused by a photocell-controlled peristaltic pump system. Intraductal pancreatic secretion was not affected by PYY at a dose of 400 pmol/kg/hr. PYY at a dose of 800 pmol/kg/hr significantly reduced the volume of pancreatic secretion and its protein and bicarbonate content. Pancreatic secretory response normalized within 24 hours. In conclusion, unstimulated pancreatic exocrine secretion can be inhibited by exogenous PYY in the rat.

Amylases↗
PubMed1996

Co-expression of nociceptor properties in dorsal root ganglion neurons from the adult rat in vitro.

The cell body of sensory neurons in vitro has been used as a model to study the electrophysiological properties of afferent terminals. A limitation of this approach has been the ability to identify the function of the neuron studied. In the present study, we have tested the hypothesis that a putative nociceptor can be identified in vitro based on the expression of properties associated with nociceptors in vivo. A combination of patch-clamp electrophysiological and immunohistochemical techniques were used to describe the expression of nociceptor properties in acutely cultured dorsal root ganglion neurons from the adult rat. These properties include: a small cell body diameter; the presence of the neuropeptides substance P and calcitonin-gene related peptide; a shoulder (inflection) on the falling phase of the somal action potential, a response to the algogenic agent capsaicin, and sensitization in response to prostaglandin E2. Our results indicate that the frequency of expression of each of these properties varies in a manner consistent with that predicted from observations made in vivo, and that when one property is present in any given neuron, the other properties are also likely to be present. These data support the suggestion that the cell body of adult rat dorsal root ganglion neurons in vitro can be used to study the electrophysiological properties of nociceptors.

Action Potentials↗