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D C Yeomans

Publications and source records attributed to D C Yeomans.

18 recordsLinked to original sources
PubMed2005

Decrease in inflammatory hyperalgesia by herpes vector-mediated knockdown of Nav1.7 sodium channels in primary afferents.

Induction of peripheral inflammation increases the expression of the Nav1.7 sodium channel in sensory neurons, potentially increasing their excitability. Peripheral inflammation also produces hyperalgesia in humans and an increase in nociceptive responsiveness in animals. To test the relationship between these two phenomena we applied a recombinant herpes simplex-based vector to the hindpaw skin of mice, which encoded both green fluorescent protein (GFP) as well as an antisense sequence to the Nav1.7 gene. The hindpaw was subsequently injected with complete Freund's adjuvant to induce robust inflammation. Application of the vector, but not a control vector encoding only GFP, prevented an increase in Nav1.7 expression in GFP-positive neurons and prevented development of hyperalgesia in both C and Adelta thermonociceptive tests. These results provide clear evidence of the involvement of an increased expression of the Nav1.7 channel in nociceptive neurons in the development of inflammatory hyperalgesia.

Animals↗
PubMed2004

Ameroid rings for gradual chronic constriction of the sciatic nerve in rats: contribution of different nerves to neuropathic pain.

Mononeuropathy was induced by placing an ameroid ring around the sciatic nerve and was compared with chronic constriction injury (CCI) of the sciatic nerve [Pain 33 (1988) 87] in rats. Mechanical allodynia was assessed and the role of sciatic and saphenous afferents (Adelta and C) in thermal hyperalgesia investigated. A shorter duration of mechanical allodynia in ameroid rats as compared to CCI rats was observed. Thermal hyperalgesia was observed in the saphenous innervated skin of the hindpaw for Adelta and C nociceptors in ameroid and for Adelta nociceptors only in CCI rats, respectively. The sciatic innervated skin showed a thermal hypoalgesia with a fast onset for Adelta afferents and a slower onset for C afferents in CCI and ameroid rats. The duration of both thermal hypo- and hyperalgesia was longer in ameroid rats. We conclude that ameroid rings are a useful tool for the investigation of long-duration hyperalgesic effects of nerve injury, as the effects were more stable and seen for a longer time (>8 weeks) as compared to the CCI model. The uninjured saphenous afferents, in particular C fibers, mediate thermal hyperalgesia after chronic constriction of the sciatic nerve using an ameroid ring.

Analysis of Variance↗
PubMed2004

Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia.

The stress-activated mitogen-activated protein kinase (MAPK) p38 is emerging as an important mediator of pain. The present study examined the possible involvement of peripheral and spinal p38 MAPK in capsaicin-induced thermal hyperalgesia. Topical capsaicin produced phosphorylation of p38 MAPK in the skin from the affected hindpaw as well as the corresponding lumbar spinal cord in a time dependent manner. Topical capsaicin produced robust C-fiber mediated thermal hyperalgesia that was inhibited by systemic, local peripheral, or central intrathecal pre-treatment with the p38 MAPK inhibitor, SD-282. Intraperitoneal SD-282 (10-60 mg/kg) significantly and dose-dependently attenuated capsaicin-induced C-fiber mediated thermal hyperalgesia. Similarly, 0.1-5mg/kg subcutaneous SD-282 in the hindpaw dose-dependently attenuated capsaicin-induced thermal hyperalgesia. Intrathecal administration of 1microg SD-282 was also anti-hyperalgesic in this model. Functionally, SD-282 decreased capsaicin-induced release of calcitonin gene related peptide in an in vitro skin release assay, consistent with a role for p38 MAPK in peripheral nerve function. These results suggest that p38 MAPK plays a role in the development of hyperalgesic states, exerting effects both centrally in the spinal cord and peripherally in sensory C fibers.

Animals↗
PubMed2002

Antibody-mediated lung endothelium targeting: in vivo model on primates.

We have recently provided evidence that angiotensin-converting enzyme (ACE) is a rational target and anti-ACE monoclonal antibodies (mAbs) are suitable molecules for directing gene/drug delivery into the pulmonary endothelium of rodents. As a step towards gene therapy clinical trials using this approach, the present study evaluated the potential of anti-ACE mAbs for in vivo lung endothelium targeting in 10 species of primates. Cross-reactivity of 10 distinct mAbs directed to human ACE with ACE from baboon, macaques, cercopithecus and chimpanzee revealed that the highest binding with ACE from baboon and macaques was with mAb i2H5, from chimpanzee - mAb 9B9, and from human - 9B9 and i2H5. Thereafter, in vivo biodistribution of mAbs i2H5 and 9B9 was estimated in Macaca arctoides. MAb i2H5, which binds to macaque ACE with substantially higher affinity than mAb 9B9, also more effectively accumulates in their lungs than mAb 9B9. Immunospecificity of lung accumulation (mAb/control IgG ratio) was 37 for i2H5 and 0.5 for 9B9. Lung selectivity of i2H5 uptake (lung/blood ratio) was around 10. Therefore mAb i2H5 may be useful for in vivo lung targeting in non-human primates, whereas 9B9 may be most useful in primates that are closer to humans (chimpanzee). A combination of these two mAbs may be particularly useful for human clinical trials of gene/drug therapy for lung disorders such as pulmonary hypertension and lung metastases.

Animals↗
PubMed2001

The combined effects of N-type calcium channel blockers and morphine on A delta versus C fiber mediated nociception.

UNLABELLED: Intrathecal mu opiates produce analgesia presynaptically by inhibiting calcium ion influx and postsynaptically by increasing potassium flux. Mu receptors are expressed on presynaptic terminals of unmyelinated (C), but not myelinated (A delta) nociceptors. Thus, mu-opioids such as morphine may act presynaptically to inhibit C, but not A delta, neurotransmission, and postsynaptically on dorsal horn cells that receive input from A delta and/or C fiber nociceptors. N-type calcium ion channel blockers, such as omega-conotoxin GVIA (omega-CTX), produce analgesia by impeding flux of calcium ions into A delta and C fiber nociceptor terminals. Thus, morphine and omega-CTX attenuated C fiber nociception additively, possibly indicating the same presynaptic site of action. Conversely, morphine and omega- CTX were supraadditively analgesic on an A delta test, indicating that these agents probably have different sites of action. We conclude that although intrathecal application of either morphine or omega-CTX attenuates both A delta and C fiber mediated nociception in rats, the combined effects are quite different for the two fiber types. Specifically, although coadministration of morphine with omega-CTX produces an additive, apparently presynaptic antinociception for C fiber-mediated responses, the combination produces a clearly supraadditive, and likely synergistic effect on A delta mediated nociception, probably by acting at pre and postsynaptic sites, respectively. IMPLICATIONS: This study demonstrates that combined spinal administration of mu opioids and N-type calcium channel blockers may be useful in providing analgesia for A delta mediated (first, sharp) pain while minimizing the side effects of both drugs.

Animals↗
PubMed2000

Genetic therapy for pain management.

Two approaches to genetic therapy for the management of chronic pain have recently been investigated in animal models of pain. First, transgene-mediated delivery of antinociceptive molecules to the cerebrospinal fluid has been performed with engineered cell lines transplanted to the subarachnoid space and with recombinant adenoviruses that transduce pia mater cells. Second, the phenotype of nociceptive neurons has been altered by recombinant herpes viruses overexpressing antinociceptive peptides or reducing expression of endogenous nociceptive molecules. Both approaches attenuate or reverse persistent nociceptive states, suggesting use in the development of genetic therapy for pain management in humans.

Genetic Therapy↗
PubMed1999

Antihyperalgesic effects of infection with a preproenkephalin-encoding herpes virus.

To test the utility of gene therapeutic approaches for the treatment of pain, a recombinant herpes simplex virus, type 1, has been engineered to contain the cDNA for an opioid peptide precursor, human preproenkephalin, under control of the human cytomegalovirus promoter. This virus and a similar recombinant containing the Escherichia coli lacZ gene were applied to the abraded skin of the dorsal hindpaw of mice. After infection, the presence of beta-galactosidase in neuronal cell bodies of the relevant spinal ganglia (lacZ-containing virus) and of human proenkephalin (preproenkephalin-encoding virus) in the central terminals of these neurons indicated appropriate gene delivery and expression. Baseline foot withdrawal responses to noxious radiant heat mediated by Adelta and C fibers were similar in animals infected with proenkephalin-encoding and beta-galactosidase-encoding viruses. Sensitization of the foot withdrawal response after application of capsaicin (C fibers) or dimethyl sulfoxide (Adelta fibers) observed in control animals was reduced or eliminated in animals infected with the proenkephalin-encoding virus for at least 7 weeks postinfection. Hence, preproenkephalin cDNA delivery selectively blocked hyperalgesia without disrupting baseline sensory neurotransmission. This blockade of sensitization was reversed by administration of the opioid antagonist naloxone, apparently acting in the spinal cord. The results demonstrate that the function of sensory neurons can be selectively altered by viral delivery of a transgene. Because hyperalgesic mechanisms may be important in establishing and maintaining neuropathic and other chronic pain states, this approach may be useful for treatment of chronic pain and hyperalgesia in humans.

Animals↗
PubMed1997

Low but not high rate noxious radiant skin heating evokes a capsaicin-sensitive increase in spinal cord dorsal horn release of substance P.

Some kinds of nociception appear to be partially mediated by the release of substance P (SP) in the spinal cord dorsal horn from terminals of primary afferent nociceptors. Only some nociceptors contain and release SP however. Specifically, SP appears to be released by unmyelinated (C) nociceptive afferents when activated by noxious stimulation to the skin, but does not appear to be contained in cutaneous myelinated (A delta) nociceptive afferents. We have proposed a model of nociception in rats that uses different rates of noxious skin heating to allow for differential assessment on behavioral responses mediated by the activation of A delta or C fiber nociceptors. As one means of testing the validity of this model we have examined the effects of using high and low rate noxious skin heating on the dorsal horn release of substance P-like immunoreactivity (SPLI) in decerebrate/spinal transected animals. Consistent with the model, low rate skin heating evokes a significant increase in dorsal horn SPLI release indicating C fiber mediation, whereas high rate skin heating did not evoke SP release, indicating mediation by afferents other than C afferents, i.e. A delta nociceptive afferents. Also consistent with behavioral effects, topical application of capsaicin, which sensitizes C nociceptors, increased the SPLI release evoked by low but not high rate skin heating. These data provide additional evidence that foot withdrawals evoked by low rate skin heating are mediated by C fiber activation, whereas foot withdrawals evoked by high rate skin heating are evoked by A delta fiber activation.

Animals↗
PubMed1997

Differential antinociceptive effects of spinal opioids on foot withdrawal responses evoked by C fibre or A delta nociceptor activation.

1. Intrathecal application of mu, delta, and kappa opioids attenuate responses on several tests of animal nociception. However, the potency of these opioids differ depending on which tests were used. One factor contributing to these discrepancies is that different types of noxious stimuli activate different sets of nociceptor types, which may be differentially sensitive to opiate inhibition. To examine this hypothesis, we used a recently developed behavioural test which allows for differential assessment of nociception evoked by the activation of myelinated (A delta) and unmyelinated C thermonociceptors. 2. Administration of a kappa-selective agonist was ineffective on either type of response. Delta1 drugs were slightly more potent on C fibre-mediated responses than on A delta-mediated responses. 3. Intrathecal mu and delta2 drugs were antinociceptive on both A delta and C nociceptor-mediated responses. However, unlike the delta1 effects, the dose-response curves for mu and delta2 drugs were significantly more steep for A delta than for C fibre-mediated responses, potentially indicating differences in the mechanisms by which the drugs act on these 2 response types.

Analgesics↗
PubMed1996

Effects of systemic morphine on responses of primates to first or second pain sensations.

Despite evidence that systemic morphine preferentially attenuates second pain sensations that are presumed to result from activation of unmyelinated (C) nociceptors, most animal models of nociception elicit sensations that result from or are dominated by activation of myelinated (A-delta) nociceptors. Therefore, methods were developed to directly compare the effects of morphine on late (second) pain sensations and early onset (first) pain sensations in an animal model. In order to establish appropriate stimulus parameters, human psychophysical experiments compared characteristics of sensations evoked by brief (pulsed) thermal stimulation and ramp-and-hold thermal stimulation. Brief (500 msec) contact of a pre-heated thermode with the skin produced late pain sensations with peripheral conduction velocities in the range of C afferents, as estimated by latencies from stimulation of proximal and distal sites on the leg. The sensations evoked by brief contact increased with successive contacts (pulses) at 0.4 Hz, demonstrating temporal summation of sensation intensity. Pretreatment of the skin with capsaicin enhanced the late pain sensations from pulsed stimulation. In contrast, peak sensations evoked by ramp-and-hold thermal stimulation were evoked at similar latencies from disparate sites on the leg, and capsaicin pretreatment of the skin did not increase the magnitude of these sensations. The pulsed and ramp-and-hold forms of stimulation were used in a paradigm designed to test for differential effects of systemic morphine on operant responses of non-human primates. Low doses of morphine reduced operant responding to pulsed thermal contact, while higher doses were required to affect responses to ramp-and-hold thermal stimulation. The low doses of morphine did not suppress non-nociceptive (intertrial) motor responses, indicating that motor inhibition was not responsible for the effects on escape responses to pulsed stimulation. Measurements of skin temperature 10 cm from the site of stimulation showed that morphine had no effect on baseline temperature but attenuated changes in skin temperature that were elicited by pulsed and by ramp-and-hold stimulation. This effect of morphine on skin temperature responses could not account for the reduction of operant responsivity to thermal stimulation. These results support previous findings that systemic morphine preferentially attenuates second pain sensations, and a new animal model of morphine-sensitive thermal nociception is established. These findings demonstrate the importance of defining the sources of afferent input and the response measures in experiments which attempt to measure antinociceptive effects of pharmacological agents.

Adult↗
PubMed1995

Comparisons of dose-dependent effects of systemic morphine on flexion reflex components and operant avoidance responses of awake non-human primates.

Electromyographic activity and the force of reflex and operant responses were recorded following administration of morphine. Low doses facilitated reflex responses to input from A-delta afferents but not from A-beta input. Higher doses inhibited A-delta responses but not A-beta responses. Operant avoidance responses to visual cues were unchanged. Thus, depending on the dose, nociceptive reflexes were facilitated or inhibited, without associated effects on non-nociceptive input or on motor output.

Animals↗
PubMed1994

Purification of rat brain, rabbit aorta, and human platelet thromboxane A2/prostaglandin H2 receptors by immunoaffinity chromatography employing anti-peptide and anti-receptor antibodies.

In the present study, a new polyclonal antibody (TxAb) was raised against native thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor protein. Previously developed anti-peptide antibodies (P1Ab, P2Ab) and TxAb were then used to prepare immunoaffinity columns to purify TXA2/PGH2 receptors from platelets, brain, and aorta. In platelets, SDS-polyacrylamide gel electrophoresis revealed the purification of a 55-kDa protein by each affinity column. Identification of this protein as the TXA2/PGH2 receptor was based on: 1) an identical electrophoretic mobility to authentic receptor; 2) immunoblotting of TxAb against P1Ab and P2Ab-purified protein; 3) immunoblotting of P1Ab/P2Ab against TxAb-purified protein; and 4) specific [3H]SQ29,548 binding to TxAb-purified protein. P1Ab/TxAb purification of receptors from brain revealed a major protein band at 55 kDa. Furthermore, the eluates from ligand affinity chromatography confirmed the presence of this 55-kDa protein in brain (which was immunoblotted with TxAb), and contained specific [3H]SQ29,548 binding. In addition to the 55-kDa protein, P1Ab/TxAb also purified a minor protein in brain at 52 kDa, which when concentrated, cross-blotted with TxAb and P1Ab. This finding indicates sequence homology between the 55- and 52-kDa proteins. Independent identification of brain TXA2/PGH2 receptors was provided by P2Ab/TxAb immunohistochemistry, which demonstrated specific labeling of discrete myelin-containing fiber tracts. P2Ab/TxAb purification of TXA2/PGH2 receptors from aorta also revealed a major protein band at 55 kDa and a minor band at 52 kDa. These results represent the first purification of TXA2/PGH2 receptors from either brain or aorta.

Animals↗
PubMed1993

The function of noradrenergic neurons in mediating antinociception induced by electrical stimulation of the locus coeruleus in two different sources of Sprague-Dawley rats.

Although noradrenergic neurons in the nucleus locus coeruleus are known to project to the spinal cord, these neurons appear to innervate different regions of the spinal cord in Sprague-Dawley rats obtained from two different vendors. Recent anatomical studies demonstrated that the noradrenergic neurons in the locus coeruleus in Sasco Sprague-Dawley rats primarily innervate the ventral horn, whereas Harlan Sprague-Dawley rats have coeruleospinal projections that terminate in the dorsal horn of the spinal cord. This report describes the results of behavioral experiments that were designed to determine the functional significance of these anatomical differences. Electrical stimulation of neurons in the locus coeruleus produced antinociception in both Harlan and Sasco rats. The antinociception in Harlan rats was readily reversed by intrathecal injection of yohimbine, a selective alpha 2-adrenoceptor antagonist, or by phentolamine, a non-selective alpha 2-adrenoceptor antagonist. In contrast, these antagonists did not alter the antinociception produced by locus coeruleus stimulation in Sasco rats. Finally, the alpha 2-antagonist, idazoxan, did not alter the antinociceptive effect of locus coeruleus stimulation in either group of rats. These observations indicate that coeruleospinal noradrenergic neurons in Harlan and Sasco Sprague-Dawley rats have different physiological functions. Thus, electrical stimulation of noradrenergic neurons in the locus coeruleus that innervate the spinal cord dorsal horn (Harlan rats) produces antinociception, but stimulation of coeruleospinal noradrenergic neurons that project to the ventral horn (Sasco rats) does not produce antinociception. It is likely that genetic differences between these outbred stocks of rats account for the fundamental differences in the projections of coeruleospinal neurons and their function in controlling nociception.

Adrenergic alpha-Antagonists↗
PubMed1992

Antinociception induced by microinjection of substance P into the A7 catecholamine cell group in the rat.

Stimulation of neurons in the ventromedial medulla produces antinociception that is mediated in part by indirect activation of pontospinal noradrenergic neurons. Substance P-containing neurons located in the ventromedial medulla project to the A7 catecholamine cell group and may serve as an excitatory link between these two cell groups. Thus, the antinociception induced by stimulation of the neurons in ventromedial medulla may be mediated by substance P released from these projections which activates spinally projecting noradrenergic neurons in the A7 cell group. This hypothesis was tested by determining whether microinjection of various doses of substance P into the A7 cell group of the rat could induce antinociception. The results indicated that substance P induced dose-dependent antinociception that was more pronounced in the hindlimb ipsilateral to the microinjections. This observation is consistent with anatomical observations that noradrenergic A7 neurons project predominantly to the ipsilateral spinal cord dorsal horn. Moreover, the antinociceptive effects of substance P microinjection appear to be mediated at least in part by activation of spinally projecting noradrenergic neurons in the A7 cell group, because intrathecal injections of the alpha-2 noradrenergic antagonists yohimbine and idazoxan blocked these antinociceptive effects. The results of these experiments support the hypothesis that the antinociception induced by stimulation of neurons in the ventromedial medulla is mediated in part by activation of substance P-containing neurons that project to, and activate, spinally projecting noradrenergic neurons located in the A7 catecholamine cell group.

Afferent Pathways↗
PubMed1991

The noradrenergic innervation of the spinal cord: differences between two substrains of Sprague-Dawley rats determined using retrograde tracers combined with immunocytochemistry.

We have recently described the spinal cord terminations of noradrenergic neurons located in the A5, A6 and A7 cell groups. However, recent reports from another laboratory, using similar experimental methods, have described results that are profoundly different. The present experiments were designed to determine whether these discrepant results are due to fundamental differences between the substrains of rats used in the conflicting experiments. To this end, retrograde tract tracing experiments were done using Sprague-Dawley rats from either Sasco, Inc. or Harlan Sprague-Dawley, Inc. The results indicate that noradrenergic neurons in the pontine catecholamine cell groups exhibit remarkably different spinal cord projections in these two substrains of Sprague-Dawley derived rats.

Animals↗
PubMed1990

Projections of substance P-immunoreactive neurons located in the ventromedial medulla to the A7 noradrenergic nucleus of the rat demonstrated using retrograde tracing combined with immunocytochemistry.

Stimulation of neurons located in the ventromedial medulla (VMM), including the nucleus raphe magnus (RMg), produces antinociception which appears to be mediated in part by activation of spinally-projecting noradrenergic neurons located in the A7 catecholamine nucleus. Although the identity of the VMM neurons that project to the A7 nucleus is not known, there is indirect evidence that these neurons contain substance P. This possibility was examined by injecting the retrograde tracer Fluoro-Gold into the A7 nucleus and determining whether substance P-immunoreactive neurons in the VMM were labeled with Fluoro-Gold. The results of these experiments demonstrated that numerous substance P-immunoreactive cells in the RMg, gigantocellular reticular nucleus pars alpha and the paragigantocellular reticular nucleus were retrogradely labeled by an injection of Fluoro-Gold into the A7 nucleus. These observations indicate that substance P-containing neurons in these areas of the VMM project to the A7 nucleus. Thus, the antinociception induced by stimulation of the VMM may be mediated by activation of substance P-containing neurons that project to and activate spinally projecting noradrenergic neurons in the A7 nucleus.

Animals↗
PubMedDate not supplied

Purification of adrenal chromaffin cells increases antinociceptive efficacy of xenotransplants without immunosuppression.

We have found that immunosuppression is necessary for the survival of xenogeneic adrenal medullary transplants. Because chromaffin cells are essentially nonimmunogenic, it is likely that the highly immunogenic "passenger" cells in the transplant preparation bring about rejection. This article describes a procedure that produces an essentially pure preparation of chromaffin cells for transplantation. Bovine adrenal medullary cells were isolated and differentially plated, resulting in a semipurified preparation of chromaffin cells. Ferromagnetic beads were added to the cell suspension, some of which were phagocytized by endothelial cells, which allowed their removal by exposure to a magnet. The remaining cells were then exposed to ferromagnetic beads coated with isolectin B4 from Griffonia simplicifolia and once again to a magnetic field. The "semipurified" preparation contained approximately 90% chromaffin cells, whereas the "highly purified" preparation was > 99.5% chromaffin cells as determined immunohistochemically. The immunogenicity of the two cell preparations was assessed in vitro by determining their capacity to evoke lymphocyte proliferation. Rat spleen lymphocytes were mixed with either a highly purified or semipurified population of bovine chromaffin cells. The results of this assay demonstrated that the highly purified preparation was a much weaker stimulant of lymphocyte proliferation than was the semipurified preparation and may demonstrate better graft survival in vivo. Transplantation via intrathecal catheter of either 80,000 or 250,000 cells from the highly or partially purified preparations onto the lumbar spinal cord of nonimmunosuppressed and non-nicotine-stimulated rats produced a cell number-dependent antinociception for both A(delta) and C fiber-mediated thermonociception at 6 days after transplantation. After 6 days and up to 28 days, only the "highly purified" preparation showed antinociception. These results suggest that nearly complete purification of bovine chromaffin cells minimizes immunorejection of xenogeneic transplants of these cells.

Adrenal Medulla↗