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T L Yaksh

Publications and source records attributed to T L Yaksh.

At least 37 records · Page 2Linked to original sources
PubMed1999

Inhibition of spinal protein kinase C reduces nerve injury-induced tactile allodynia in neuropathic rats.

We investigated the effects of inhibiting spinal protein kinases including PKC, PKA and PKG on tactile allodynia in rats with a unilateral tight ligation on L5/L6 spinal nerves (Chung model). The intrathecal (IT) delivery of GF109203X, a PKC inhibitor, produced a potent and long lasting anti-allodynic effect. The effect was dose-dependent and stereospecific. Bisindolymaleimide V, an inactive homologue of GF, had no effect. Additionally, two other PKC inhibitors, PKC19-31 and chelerythrine, displayed significant anti-allodynic action. Spinal PKA, but not PKG, is likely involved in Chung tactile allodynia, since H89 (a PKA inhibitor) showed anti-allodynic activity, while KT5823 (a PKG inhibitor) had only a minor effect. These data emphasize that spinal PKC plays an important role in nerve injury-induced tactile allodynia. Other protein kinases such as PKA may also contribute to this phenomenon.

Animals↗
PubMed1999

Mechanical allodynia in rats is blocked by a Ca2+ permeable AMPA receptor antagonist.

Mild thermal injury to the hindpaw induces tactile allodynia distal to the injury. The allodynia is blocked by non-NMDA, but not NMDA, antagonists. The calcium permeable subtype of non-NMDA receptors is blocked by Joro spider toxin (JSTX). We injected JSTX or saline intrathecally followed after 5 min, 6 or 24 h by thermal injury. Rats receiving saline had decreased mechanical thresholds. Rats receiving 3 microg JSTX 5 min or 6 h prior to burn showed no allodynia. JSTX had no prominent side effects at doses between 1 and 5 microg. JSTX (5 microg) had no effect on thermal threshold. These results are consistent with the hypothesis that spinal mechanisms leading to tactile allodynia in this injury model act via a calcium permeable AMPA linkage.

Animals↗
PubMed1999

Neuronal nitric oxide synthase mRNA upregulation in rat sensory neurons after spinal nerve ligation: lack of a role in allodynia development.

Pharmacological evidence suggests a functional role for spinal nitric oxide (NO) in the modulation of thermal and/or inflammatory hyperalgesia. To assess the role of NO in nerve injury-induced tactile allodynia, we examined neuronal NO synthase (nNOS) expression in the spinal cord and dorsal root ganglia (DRG) of rats with tactile allodynia because of either tight ligation of the left fifth and sixth lumbar spinal nerves or streptozotocin-induced diabetic neuropathy. RNase protection assays indicated that nNOS mRNA (1) was upregulated in DRG, but not spinal cord, neurons on the injury side beginning 1 d after nerve ligation, (2) peaked (approximately 10-fold increase) at 2 d, and (3) remained elevated for at least 13 weeks. A corresponding increase in DRG nNOS protein was also observed and localized principally to small and occasionally medium-size sensory neurons. In rats with diabetic neuropathy, there was no significant change in DRG nNOS mRNA. However, similar increases in DRG nNOS mRNA were observed in rats that did not develop allodynia after nerve ligation and in rats fully recovered from allodynia 3 months after the nerve ligation. Systemic treatment with a specific pharmacological inhibitor of nNOS failed to prevent or reverse allodynia in nerve-injured rats. Thus, regulation of nNOS may contribute to the development of neuronal plasticity after specific types of peripheral nerve injury. However, upregulation of nNOS is not responsible for the development and/or maintenance of allodynia after nerve injury.

Animals↗
PubMed1999

Generation and analysis of GluR5(Q636R) kainate receptor mutant mice.

The physiological significance of RNA editing of transcripts that code for kainate-preferring glutamate receptor subunits is unknown, despite the fact that the functional consequences of this molecular modification have been well characterized in cloned receptor subunits. RNA editing of the codon that encodes the glutamine/arginine (Q/R) site in the second membrane domain (MD2) of glutamate receptor 5 (GluR5) and GluR6 kainate receptor subunits produces receptors with reduced calcium permeabilities and single-channel conductances. Approximately 50% of the GluR5 subunit transcripts from adult rat brain are edited at the Q/R site in MD2. To address the role of glutamate receptor mRNA editing in the brain, we have made two strains of mice with mutations at amino acid 636, the Q/R-editing site in GluR5, using embryonic stem cell-mediated transgenesis. GluR5(RloxP/RloxP) mice encode an arginine at the Q/R site of the GluR5 subunit, whereas GluR5(wt(loxP)/wt(loxP)) mice encode a glutamine at this site, similar to wild-type mice. Mutant animals do not exhibit developmental abnormalities, nor do they show deficits in the behavioral paradigms tested in this study. Kainate receptor current densities were reduced by a factor of six in acutely isolated sensory neurons of dorsal root ganglia from GluR5(RloxP/RloxP) mice compared with neurons from wild-type mice. However, the editing mutant mice did not exhibit altered responses to thermal and chemical pain stimuli. Our investigations with the GluR5-editing mutant mice have therefore defined a set of physiological processes in which editing of the GluR5 subunit is unlikely to play an important role.

Animals↗
PubMed1999

The spinal biology in humans and animals of pain states generated by persistent small afferent input.

Behavioral models indicate that persistent small afferent input, as generated by tissue injury, results in a hyperalgesia at the site of injury and a tactile allodynia in areas adjacent to the injury site. Hyperalgesia reflects a sensitization of the peripheral terminal and a central facilitation evoked by the persistent small afferent input. The allodynia reflects a central sensitization. The spinal pharmacology of these pain states has been defined in the unanesthetized rat prepared with spinal catheters for injection and dialysis. After tissue injury, excitatory transmitters (e.g., glutamate and substance P) acting though N-methyl-D-aspartate (NMDA) and neurokinin 1 receptors initiate a cascade that evokes release of (i) NO, (ii) cyclooxygenase products, and (iii) activation of several kinases. Spinal dialysis show amino acid and prostanoid release after cutaneous injury. Spinal neurokinin 1, NMDA, and non-NMDA receptors enhance spinal prostaglandin E2 release. Spinal prostaglandins facilitate release of spinal amino acids and peptides. Activation by intrathecal injection of receptors on spinal C fiber terminals (mu,/delta opiate, alpha2 adrenergic, neuropeptide Y) prevents release of primary afferent peptides and spinal amino acids and blocks acute and facilitated pain states. Conversely, consistent with their role in facilitated processing, NMDA, cyclooxygenase 2, and NO synthase inhibitors act to diminish only hyperalgesia. Importantly, spinal delivery of several of these agents diminishes human injury pain states. This efficacy emphasizes (i) the role of facilitated states in humans, (ii) shows the importance of spinal systems in human pain processing, and (iii) indicates that these preclinical mechanisms reflect processes that regulate the human pain experience.

Afferent Pathways↗
PubMed1999

Spinal systems and pain processing: development of novel analgesic drugs with mechanistically defined models.

Much research has been undertaken in the field of pain in an attempt to find an effective treatment. Insights into the underlying mechanisms of pain have been gained from studies using preclinical animal models (acute stimuli, post-tissue injury and peripheral nerve injury) and evaluating their similarity with the human condition. In this article, these pain models are summarized and the mechanisms of pain discussed in relation to spinal processing. In the context of this research the therapeutic potential of novel analgesics is highlighted as the future looks forward to the many possibilities that the targeted spinal delivery of drugs can bring.

Afferent Pathways↗
PubMed1999

Intrathecal substance P-induced thermal hyperalgesia and spinal release of prostaglandin E2 and amino acids.

Substance P is an important neuromediator in spinal synaptic transmission, particularly in processing nociceptive afferent information. The effects of substance P are mediated by activation of the neurokinin 1 receptor. Evidence has suggested that excitatory amino acids such as glutamate, and prostaglandins including prostaglandin E2 are involved in the enhanced spinal excitability and hyperalgesia produced by spinal substance P. In the present study, we have demonstrated that intrathecal injection of substance P (20 nmol) in rats chronically implanted with intrathecal dialysis catheters induced a decrease in thermal paw withdrawal latency (before: 10.4+/-0.3 s; after 7.6+/-0.6 s), which was accompanied by an increase in prostaglandin E2 (362+/-37% of baseline), glutamate (267+/-84%) and taurine (279+/-57%), but not glycine, glutamine, serine or asparagine. Intrathecal injection of artificial cerebrospinal fluid had no effect upon the behavior or release. Substance P-induced thermal hyperalgesia and prostaglandin E2 release were significantly attenuated by a selective neurokinin 1 receptor antagonist RP67580, but not by an enantiomer RP68651. However, substance P-induced release of glutamate and taurine was not reduced by treatment with RP67580. SR140333, another neurokinin 1 receptor antagonist, displayed the same effects as RP67580 (i.e. block of thermal hyperalgesia and prostaglandin E2 release, but not release of amino acids). These results provide direct evidence suggesting that the spinal substance P-induced thermal hyperalgesia is mediated by an increase in spinal prostaglandin E2 via activation of the neurokinin 1 receptor. These findings define an important linkage between small afferents, sensory neurotransmitter release and spinal prostanoids in the cascade of spinally-mediated hyperalgesia. The evoked release of glutamate is apparently not a result of activation of neurokinin 1 receptors. Accordingly, consistent with other pharmacological data, acute spinal glutamate release does not contribute to the hyperalgesia induced by activation of spinal neurokinin 1 receptors.

Amino Acids↗
PubMed1999

In vitro prostanoid release from spinal cord following peripheral inflammation: effects of substance P, NMDA and capsaicin.

1. Spinal prostanoids are implicated in the development of thermal hyperalgesia after peripheral injury, but the specific prostanoid species that are involved are presently unknown. The current study used an in vitro spinal superfusion model to investigate the effect of substance P (SP), N-methyl-d-aspartate (NMDA), and capsaicin on multiple prostanoid release from dorsal spinal cord of naive rats as well as rats that underwent peripheral injury and inflammation (knee joint kaolin/carrageenan). 2. In naive rat spinal cords, PGE2 and 6-keto-PGF1alpha, but not TxB2, levels were increased after inclusion of SP, NMDA, or capsaicin in the perfusion medium. 3. Basal PGE2 levels from spinal cords of animals that underwent 5-72 h of peripheral inflammation were elevated relative to age-matched naive cohorts. The time course of this increase in basal PGE2 levels coincided with peripheral inflammation, as assessed by knee joint circumference. Basal 6-keto-PGF1alpha levels were not elevated after injury. 4. From this inflammation-evoked increase in basal PGE2 levels, SP and capsaicin significantly increased spinal PGE2 release in a dose-dependent fashion. Capsaicin-evoked increases were blocked dose-dependently by inclusion of S(+) ibuprofen in the capsaicin-containing perfusate. 5. These data suggest a role for spinal PGE2 and NK-1 receptor activation in the development of hyperalgesia after injury and demonstrate that this relationship is upregulated in response to peripheral tissue injury and inflammation.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

The effect of intrathecal gabapentin on pain behavior and hemodynamics on the formalin test in the rat.

UNLABELLED: In this study, we examined the effect of intrathecal (i.t.) gabapentin, administered before and after the injection of formalin into the rat hindpaw, on pain behavior and hemodynamics. Formalin evoked a biphasic flinching behavior and hypertension. I.t. gabapentin administered 10 min before formalin produced a dose-dependent reduction of the Phase 2, but not Phase 1, flinching and cardiovascular response. In contrast, i.t. gabapentin administered 9 min after formalin had no effect on either phase of flinching. I.t. D-serine (100 micrograms) administered 10 min before i.t. galapentin reversed the Phase 2 effect of gabapentin. I.t. gabapentin did not affect the thermal escape latency or the baseline cardiovascular measures even at the largest dose (300 micrograms). These results indicate that the spinal effect of gabapentin reduces the somatosympathetic reflex and somatosensory response to tissue injury without an accompanying effect on acute nociception or resting sympathetic outflow. IMPLICATIONS: After tissue injury, there is an enhanced pain behavior and cardiovascular response, representing a facilitated state of spinal processing. Spinally delivered gabapentin had no evident effect on resting heart rate or blood pressure, but it attenuated the enhanced pain behavior and cardiovascular response otherwise produced by injury.

Acetates↗
PubMed1999

Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist--loperamide.

BACKGROUND: Preclinical and clinical evidence indicates that locally administered opioid agonists produce an antihyperalgesic effect through peripheral opioid receptors in inflamed tissue. Loperamide, a mu opioid agonist, does not cross the blood-brain barrier and therefore lacks central effects after systemic administration. The authors defined the effects of topical loperamide on a thermal injury-induced hyperalgesia. METHODS: In halothane-anesthetized rats, thermal injury was induced by placing the plantar surface of a hindpaw on a hot plate (52.0+/-1 degrees C) for 45 s. Loperamide was prepared in a cream emulsion (ADL 2-1294B, 0.5%, 1.7%, and 5.0%). The drug was applied as follows: before or after injury on the injured paw and on a normal paw and after injury on the injured paw of morphine-tolerant rats. Paw withdrawal latency to a radiant heat source was measured to determine the nociceptive threshold. A pharmacokinetic study was performed with the use of 14C-labeled drug. RESULTS: Thermal injury yielded a significant thermal hyperalgesia. Loperamide, but not the vehicle, posttreatment on the injured paw resulted in a dose-dependent antihyperalgesic effect, which was reversible with naloxone (1 mg/kg given intraperitoneally). Treatment with loperamide on the normal paw produced short-lasting hypoalgesia, but the effect was not reversible with naloxone. Pretreatment at 1 and 2 but not 4 h with loperamide was effective. A rightward shift of the dose-response curve was observed in rats made tolerant to systemic morphine with subcutaneous morphine pellets. No rats with drug treatment displayed any evident behavior changes (eg., loss of corneal or pinna reflexes or change in ambulation). Drug activity in the tissue revealed an elimination half life of 2.3 h and negligible concentration in the blood. CONCLUSIONS: Loperamide, a peripherally acting mu opioid agonist, applied topically at the site of inflammation possesses a significant antihyperalgesic action without any systemic side effects.

Analgesics↗
PubMed1999

Pharmacokinetics and efficacy of epidurally delivered sustained-release encapsulated morphine in dogs.

BACKGROUND: We evaluated the epidural effects of a multivesicular liposome-based sustained-release preparation of morphine (C0401) on behavior and lumbar cerebrospinal fluid and serum kinetics of morphine. METHODS: Beagle dogs were prepared with lumbar epidural catheters with subcutaneous injection ports and lumbar intrathecal catheters. Each dog (n = 6) received the following by the epidural route: 5 mg/3 ml morphine sulfate in saline (MS-5), 10 mg/3 ml C0401 (C0401-10), and 30 mg/3 ml C0401 (C0401-30). Behavioral and physiologic parameters and nociceptive responses (skin twitch latency) were evaluated, and morphine concentrations were determined in lumbar cerebrospinal fluid and serum. RESULTS: All morphine treatments blocked the skin twitch response. Time to onset was 1.3 +/- 0.3 h for C0401-30; 2.6 +/- 0.6 h for C0401-10; and 0.4 +/- 0.2 h for MS-5. Duration of action was 62 +/- 0.3 h for C0401-30; 27 +/- 2 h for MS-5. All treatments produced a modest reduction in arousal, muscle tone, and coordination, with the duration of the C0401-30 preparation being longer lasting. Respiratory rate was mildly depressed by all treatments, and moderate hypotension was noted. Time to peak cerebrospinal fluid morphine concentration was 11 h for C0401-30; 3 h for C0401-10; and 5 min for MS-5. Peak lumbar cerebrospinal fluid level was 34,992 +/- 5,578 ng/ml for MS-5; 14,483 +/- 3,438 ng/ml for C0401-30; and 10,730 +/- 2,888 ng/ml for C0401-10. Morphine mean residence time in lumbar cerebrospinal fluid was 0.8 +/- 0.1 h for MS-5; 8.9 +/- 1.0 h for C0401-30. DISCUSSION: Kinetics studies showed that multivesicular liposome sequestration results in a restrained and persistent release of morphine from the epidural space. This extended release corresponded with an extended duration of analgesia without an attendant increase in the incidence of side effects.

Analgesics, Opioid↗
PubMed1999

Preclinical toxicity screening of intrathecal adenosine in rats and dogs.

BACKGROUND: Intrathecally administered adenosine receptor agonists have antinociceptive effects in animals, suggesting that intrathecal adenosine might provide analgesia in humans. The authors performed preclinical neurotoxicity studies to define the safety of intrathecally administered adenosine in rats and dogs. METHODS: Eighteen rats with long-term intrathecal catheters received daily injections of saline or 100 microg adenosine for 4 days and were observed for general behavior and thermal nociception before being killed on day 6. Nine beagle dogs were prepared with long-term, lumbar intrathecal catheters and infused continuously with saline or adenosine, 2.4 mg/day for 48 h, then 7.2 mg/day for 26 days. Animals were then anesthetized and perfused with preservative and their spinal cords were examined systematically. RESULTS: No disturbances in neurologic function were detected in either animal species. intrathecal adenosine caused transient sedation in rats and increased muscle tone in dogs, resolving with continued exposure to drug. Neither adenosine-nor saline-treated rats or dogs showed acute thermal analgesia. Adenosine groups did not differ from saline groups regarding histopathology, although a moderate fibrotic and inflammatory reaction was noted in both, and protein concentrations in cerebrospinal fluid were increased in both. CONCLUSION: The current study in rats and dogs failed to provide behavioral or histologic evidence of neurotoxicity from intrathecal administration of adenosine. This provides evidence for the presumption of safety of adenosine in this dose range, and supports phase I safety trials of acute intrathecal adenosine administration in humans.

Adenosine↗
PubMed1999

Evaluation of interaction between gabapentin and ibuprofen on the formalin test in rats.

BACKGROUND: Gabapentin is active in the regulation of facilitated pain states evoked by tissue injury. The mechanism of this action is believed to be through a specific binding site, likely at the spinal level. Nonsteroidal antiinflammatory drugs have a comparable behavioral profile, although their actions are believed to be mediated by cyclooxygenase inhibition at the spinal level. This study was undertaken to determine the nature of the interaction of these two mechanistically distinct antihyperalgesic agents in rats in a model of facilitated processing, the formalin test. METHODS: The effects of intraperitoneal gabapentin and ibuprofen were examined on flinching behavior and cardiovascular response (mean arterial blood pressure [MABP] and heart rate measured in the tail artery) evoked by the injection of formalin (5%; 50 microl). Their interaction was characterized using an isobolographic analysis. RESULTS: Injection of formalin into the hind paw caused a biphasic flinching and parallel increases in MABP. Gabapentin and ibuprofen produced a limited effect on the flinching in phase 1, but both drugs produced dose-dependent suppression of the flinching observed during phase 2 (gabapentin ED50 = 88 mg/kg; ibuprofen ED50 = 19 mg/kg). Gabapentin similarly showed a dose-dependent suppression of the MABP and heart rate response only during phase 2; ibuprofen showed dose-dependent reduction of MABP response in both phases. The isobolographic analysis carried out using equipotent dose ratios in phase 2 revealed an additive interaction between the two drugs. Neither gabapentin nor ibuprofen affected the baseline cardiovascular measures. CONCLUSION: Gabapentin and ibuprofen independently alter the facilitated state as measured by somatomotor and autonomic response. Together these agents interact in an additive fashion if delivered concurrently. This combination may prove useful in managing postinjury pain states in humans.

Acetates↗
PubMed1998

A novel model of primary and secondary hyperalgesia after mild thermal injury in the rat.

Secondary hyperesthesia was investigated in a rat thermal injury model. After a mild focal thermal injury (52 degrees C/45 s) to the rat heel, the response latency for a thermal stimulus directed at the injured site was reduced (10 --> 6 s; e.g. primary thermal hyperalgesia) but no change was seen at the distal site. Conversely, tactile threshold at the distal site was significantly reduced (15 --> 5 g; e.g. secondary tactile allodynia) but much less so at the injured site. Magnitude of the secondary tactile allodynia paralleled the severity of the primary injury. Accordingly, this model has the same characteristics seen in human post-tissue-injury hyperesthetic states and provides a tool for the study of mechanisms underlying primary and secondary hyperesthesia.

Animals↗
PubMed1998

Synthesis and biological activity of a novel methylamine-bridged enkephalin analogue (MABE): a new route to cyclic peptides and peptidomimetics.

The synthesis and biological activity of a methylamine-bridged enkephalin analogue (MABE) is presented. The key step in the synthesis of the target compound involves the ring opening of Cbz-d-serine beta-lactone with Boc-Phe-NHCH2CH2NHCH3. Further synthetic elaboration of the resulting building block yielded compound 1 (MABE, Tyr-c[(NbetaCH3)-D-A2pr-Gly-Phe-NHCH2CH2-], where A2pr is a 2,3-diaminopropionic acid residue). Utilizing a combination of NMR and molecular modeling, the structure-biological activity relationships for compound 1 were studied. Using an in vitro isolated receptor assay, MABE was found to have affinities for isolated mu delta, and kappa opioid receptors of 1.6, 2.1, and 340 nM, respectively. By an in vivo thermal escape assay, MABE was found to have an ED50 of 0.027 microg in the rat when administered intrathecally. This effect was reversed by naloxone. By comparison, DAMGO, morphine, and DPDPE were found to yield ED50 values of 0.14, 2.4, and 54 microg, respectively, in the same assay.

Analgesics, Opioid↗
PubMed1998

Neurodegeneration induced by reversed microdialysis of NMDA; a quantitative model for excitotoxicity in vivo.

This study characterizes a quantifiable in vivo model of excitotoxicity. In halothane anesthetized rats, microdialysis probe was implanted into somatosensory cortex/striatum and perfused by various concentrations (1, 10, 50 and 100 mmol/l) of N-methyl-d-aspartate (NMDA) for 20 min. After 24 h, histological quantification confirmed that NMDA produced a concentration-dependent excitotoxic lesion. With 10 mmol/l NMDA, coadministration of magnesium reduced significantly, and 2-amino-5-phosphonovalerate blocked completely the development of excitotoxic injury.

2-Amino-5-phosphonovalerate↗