Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The analgesia effects of intrathecal adenosine A1 receptor agonist, R-PIA, on the hyperalgesia and CSF-glutamate release after formalin injection into the rat paw were evaluated. R-PIA significantly and dose-dependently attenuated increases in flinching behavior, and this attenuating effect was reversed by the adenosine A1 receptor antagonist, aminophylline. Morphine blocked flinchs, however MK-801 partially abolished. The increase in CSF-glutamate release evoked by formalin stimulation was inhibited by morphine but not by either R-PIA or MK-801. These findings suggest that the intrathecal adenosine A1 receptor agonist provokes analgesic effect via the postsynaptic action independent of an effect upon spinal glutamate release.
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PMID:Intrathecal adenosine A1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat. 1273 30

In <25 years, intrathecal administration of opioids (i.e. spinal analgesia) has evolved from an experimental model into an important therapy for obstetric analgesia and anaesthesia. A small dose of opioid delivered into the CSF provides almost immediate relief from labour pain with minimal risks to the mother and fetus. Careful attention, and prompt treatment when needed, can ameliorate the adverse effects of fetal bradycardia, respiratory depression and pruritus. The major limitation of intrathecal opioids for labour analgesia is the short duration of effect: 90-180 minutes under ideal circumstances. To address this problem, and to increase flexibility for anaesthesia as well as analgesia, the combined spinal-epidural (CSE) technique was developed. The CSE technique involves injection of drugs into the CSF and placement of an epidural catheter. An intrathecally administered opioid provides a rapid onset of labour analgesia without motor block or significant haemodynamic perturbation. The epidural catheter allows ongoing administration of medications to maintain labour analgesia and provides a means of delivering anaesthesia for operative delivery. This review will focus on intrathecally administered opioids as used as part of CSE analgesia. Considerable research has focused on the optimum dose of opioids when delivered intrathecally, with or without adjuncts, in the CSE technique. Fentanyl and sufentanil, two of the lipophilic synthetic opioids, have emerged as the most useful. Bupivacaine, a long-acting local anaesthetic, is often added to prolong the duration of analgesia, although this tends to increase the likelihood of motor blockade of the lower extremities. Comparisons of the CSE technique with standard epidural practices have shown that both are effective means of providing analgesia during labour. Controversy revolves around the incidence of fetal bradycardia following CSE and whether this phenomenon increases the rate of operative deliveries. The rapid onset of analgesia with intrathecally administered opioids must be balanced against the added risks of dural puncture and considered in the context of the whole duration of labour. Ultimately, the decision to choose a CSE technique depends on the experience of the anaesthesia provider and the local availability of drugs, equipment and monitoring capabilities.
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PMID:Intrathecal opioids for combined spinal-epidural analgesia during labour. 1296 28

Like opioid tolerance, neuropathic pain syndrome manifested by hyperalgesia and allodynia responds poorly to opioids. Hitherto, its development is still not clear and its treatment and prevention are still disputable. Pertussis toxin (PTX) which ADP-ribosylates the alpha-subunit of inhibitory guanine nucleotide binding regulatory proteins (Gi/Go), is used to induce morphine tolerance through intrathecal (i.t.) injection. It decreases the antinociceptive effect of opioid receptor agonists, and produces a thermal hyperalgesia as well. With treatment of PTX the inhibitory Gi- and Go-proteins signal transduction is inactivated. Inhibition of the inhibitory system would likely lead to a predominance of the excitatory system. Intrathecal PTX administration has also been suggested as a model for study of the central mechanisms of neuropathic pain. In our previous studies, with intrathecal microdialysis and drug delivery techniques, we correlated the biochemical and pharmacological effects on the behavioral expressions of i.t. PTX-treated rats. Intrathecal PTX administration would induce thermal hyperalgesia in rats, with accompaniments of a prolonged increase in the concentrations of excitatory amino acids (EAAs), glutamate and aspartate, and a decrease in the concentration of the inhibitory amino acid (IAA) glycine in the spinal CSF dialysates. The PTX-induced thermal hyperalgesia peaked between day 2 and 4, but no cold allodynia is observed; i.t. administration of N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosponovaleric acid (D-AP5), glycine and protein kinase C (PKC) inhibitor chelerythrine attenuated the thermal hyperalgesia. The PKC gamma content of both synaptosomal and cytosolic fractions were significantly increased in PTX-treated rats. In contrast, the levels of PKC alpha, beta I, or beta II isozymes in these fractions were unaffected. Infusion of NMDA antagonist D-AP5 prevented both the thermal hyperalgesia and the increase in PKC gamma expression in PTX-treated rats. Similar to our previous report, i.t. PTX reduced morphine's analgesic effect. PKC inhibitor chelerythrine attenuated this reduction of morphine's analgesia, and an inhibition of the morphine-evoked EAAs release was observed in PTX-treated rats as well. Taken together, i.t. PTX-induced neuropathic pain syndrome is accompanied by increasing of EAAs, decreasing of IAA release, and a selective increasing of PKC gamma expression in the spinal cord. Inhibition of PKC not only blocked thermal hyperalgesia, but also reversed the reduction of morphine's analgesic effect in PTX-rats. These results suggest that PTX-induced neuropathic pain syndromes are involved in EAAs, IAAs and PKC alternations.
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PMID:Implications of intrathecal pertussis toxin animal model on the cellular mechanisms of neuropathic pain syndrome. 1476 16

The present experiments examined the role of spinal proinflammatory cytokines [interleukin-1beta (IL-1)] and chemokines (fractalkine) in acute analgesia and in the development of analgesic tolerance, thermal hyperalgesia, and tactile allodynia in response to chronic intrathecal morphine. Chronic (5 d), but not acute (1 d), intrathecal morphine was associated with a rapid increase in proinflammatory cytokine protein and/or mRNA in dorsal spinal cord and lumbosacral CSF. To determine whether IL-1 release modulates the effects of morphine, intrathecal morphine was coadministered with intrathecal IL-1 receptor antagonist (IL-1ra). This regimen potentiated acute morphine analgesia and inhibited the development of hyperalgesia, allodynia, and analgesic tolerance. Similarly, intrathecal IL-1ra administered after the establishment of morphine tolerance reversed hyperalgesia and prevented the additional development of tolerance and allodynia. Fractalkine also appears to modulate the effects of intrathecal morphine because coadministration of morphine with intrathecal neutralizing antibody against the fractalkine receptor (CX3CR1) potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Fractalkine may be exerting these effects via IL-1 because fractalkine (CX3CL1) induced the release of IL-1 from acutely isolated dorsal spinal cord in vitro. Finally, gene therapy with an adenoviral vector encoding for the release of the anti-inflammatory cytokine IL-10 also potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Taken together, these results suggest that IL-1 and fractalkine are endogenous regulators of morphine analgesia and are involved in the increases in pain sensitivity that occur after chronic opiates.
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PMID:A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. 1531 61

Endothelin (ET) type A receptor antagonists enhance morphine-induced antinociception and restore morphine analgesia in morphine tolerant rats [Peptides 23 (2002) 1837; Peptides 24 (2003) 553]. These studies suggest that the central ET and opioid systems functionally interact. To explore this idea further, we determined the effect of i.c.v. administration of anti-ET-1 IgG (rabbit) on brain opioid receptor and ET receptor expression. Three days after implanting cannula into the lateral ventricle, male Sprague-Dawley rats were administered 10 microl (i.c.v.) of either control rabbit IgG (2.5 microg/microl) or anti-ET IgG (2.5 microg/microl) on day 1, day 3, and day 5. On day 6, animals were killed and the caudate and hippocampus collected. Anti-ET IgG had no significant effect on expression, measured by Western blots, of mu, delta or ET-B receptors, but increased kappa opioid (59%) and ET-A (33%) receptor protein expression in the caudate. [35S]-GTP-gamma-S binding assays demonstrated that anti-ET IgG decreased [D-Ala2-MePhe4, Gly-ol5]enkephalin efficacy, but not potency in the caudate. Control experiments showed that there was no detectable rabbit IgG in caudate and hippocampal samples. These results suggest that ET in the CSF negatively regulates kappa opioid and ET-A receptors in certain brain regions. These findings support the hypothesis that CSF neuropeptides have regulatory effects and further demonstrate a link between ET and the opioid receptor system.
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PMID:Intracerebroventricular administration of anti-endothelin-1 IgG selectively upregulates endothelin-A and kappa opioid receptors. 1554 96

In parturients, extension of epidural analgesia to include the sacral roots is necessary for adequate analgesia during the second stage of labour and for vacuum extraction and forceps delivery. There is clinical evidence that if the sitting position is adopted after local anaesthetic administration, it impairs the sacral spread of analgesia. An in vitro model representing the lumbar spinal canal has been used to demonstrate how, in the vertical position, a CSF plug can prevent downward spread of local anaesthetic. With the model tilted 25 degrees to the horizontal and also in the full horizontal position downward spread occurs. The effect of a 25 degrees head up tilt on sacral spread of epidural analgesia was compared clinically with the horizontal position. Women requesting epidural analgesia during labour were randomly allocated to receive the first epidural dose either with the head end of the bed tilted 25 degrees head up (n = 30) or remaining horizontal (n = 30). All epidurals were sited at L3/4, a test dose of 2 ml of 0.5% bupivacaine was followed by a main dose of 6 ml of 0.5% bupivacaine. Sacral sensory blockade was greater in the head up group. The difference was significant on the left side (P < 0.05) at 15, 20, and 30 minutes after the main dose. There were more patients with blocks extending to S5 (on either the left or right sides) in the head up group at 15, 20 and 30 minutes (P < 0.05 at 20 and 30 minutes on left side).
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PMID:The effect of position on sacral spread of epidural analgesia. 1563 7

Sucrose ingestion has been shown to alleviate pain and distress in rats, human infants as well as adults. Sucrose induced analgesia is related to the reward value associated with its sweet taste. The sweet taste of sucrose is a stimulus for the activation of endogenous opioid pool. The opioids in turn modulate pain perception. It has been demonstrated in a number of animal and human studies that sucrose ingestion increases the hypothalamic/CSF opioid levels. This gains support from the results obtained from naloxone challenge test, a neuro-endocrine method for assessment of endogenous opioid tone. Moreover, the analgesic effects of sucrose can be reversed by administration of opioid antagonists such as naloxone. On the other hand, long-term sucrose ingestion leads to hyperalgesia in rats and it has been hypothesized to result from a complex interaction of sucrose with the endogenous opioid system leading to a deficiency of opioids. In the present article mechanisms underlying sucrose induced analgesia including the interaction of the palatability and reward value of food with the neural substrates and its neuro-chemical basis have been reviewed in the light of both animal and human studies. In addition, clinical application of the knowledge about sucrose and its modulatory effect on the endogenous opioid system has been suggested.
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PMID:Antinociceptive effect of sucrose ingestion in the human. 1657 91

Neuraxial drug administration describes techniques that deliver drugs in close proximity to the spinal cord, i.e. intrathecally into the CSF or epidurally into the fatty tissues surrounding the dura, by injection or infusion. This approach was initially developed in the form of spinal anaesthesia over 100 years ago. Since then, neuraxial drug administration has evolved and now includes a wide range of techniques to administer a large number of different drugs to provide anaesthesia, but also analgesia and treatment of spasticity in a variety of acute and chronic settings. This review concentrates on the pharmacological agents used and the clinical basis behind currently utilised approaches to neuraxial drug administration. With regard to local anaesthetics, the main focus is on the development of the enantiomer-specific compounds ropivacaine and levobupivacaine, which provide similar efficacy to bupivacaine with a reduced risk of severe cardiotoxicity. Opioids are the other group of drugs widely used neuraxially, in particular to provide analgesia alone or more commonly in combination with other agents. The physicochemical properties of the various opioids explain the main differences in efficacy and safety between these drugs when used intrathecally, of which morphine, fentanyl and sufentanil are most commonly used. Another group of drugs including clonidine, dexmedetomidine and epinephrine (adrenaline) provide neuraxial analgesia via alpha-adrenergic receptors and are used mainly as adjuvants to local anaesthetics and opioids. Furthermore, intrathecal baclofen is in routine clinical use to treat spasticity in a number of neurological conditions. Beside these established approaches, a wide range of other drugs have been assessed for neuraxial administration to provide analgesia; however, most are in various early stages of investigation and are not used routinely. These drugs include neostigmine, ketamine, midazolam and adenosine, and the conotoxin ziconotide. The latter is possibly the most unusual compound here; it has recently gained registration for intrathecal use in specific chronic pain conditions.
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PMID:Neuraxial drug administration: a review of treatment options for anaesthesia and analgesia. 1704 29

Sex differences are observed in the development of tolerance to the antinociceptive effect of opioid drugs such as morphine, but the precise underlying mechanism remains unclear. There are evidences about the interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. We examined the sex differences and the role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. A microdialysis probe was implanted into the left nucleus accumbens core of rats and CSF (cerebrospinal fluid) dialysates were collected. The concentration of glutamate was measured by high-performance liquid chromatography with a fluorescence detector. The results showed that after chronic morphine administration, tolerance to antinociceptive effects of morphine was significantly greater in male rats (P<0.001). Sex differences in tolerance to morphine disappeared with gonadectomy of animals. There was also a significant sex difference in the glutamate level in the nucleus accumbens of morphine tolerant rats (P<0.001), ovariectomy of female rats decreased the glutamate level significantly (P<0.001), while gonadectomy did not change the glutamate level in males significantly. In conclusion, these experiments demonstrate that the excitatory amino acid release in the nucleus accumbens may be modulated by an estrogen-sensitive mechanism and play a role in the morphine analgesia and tolerance.
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PMID:Sex differences and role of gonadal hormones on glutamate level in the nucleus accumbens in morphine tolerant rats: a microdialysis study. 1711 8

Pharmacokinetics (PK)-pharmacodynamics (PD) modeling, the mathematical description of the relationship between PK and PD, can estimate and predict relevant parameters associated with onset, magnitude and time courses of dose-concentration-effect of a drug. In this report, we introduce a new nonsteady-state and time-dependent PK-PD modeling of a single dose of morphine in which time courses of concentration of unconjugated and estimated conjugated morphine in compartments of either plasma or biophase (cerebrospinal fluid, CSF) and multiple anti-nociceptive effects across thermal and mechanical stimulus modalities in rats were studied. The results showed that: (1) both intragastric and intraperitoneal administration of a single dose of morphine resulted in a differential anti-nociceptive effect in both magnitude and time course of the drug between thermal and mechanical painful stimuli (anti-mechanical pain effect was 2-3 fold stronger than anti-thermal pain effect, P < 0.01); (2) the PK data showed that the area under concentration-time curves of conjugated morphine was 4.5 and 2.0 fold bigger than unconjugated morphine in either plasma and biophase compartments, suggesting that the PK processes of unconjugated morphine are different from that of conjugated morphine; (3) the PD data also showed a change in PD characteristics of unconjugated and conjugated morphine across systemic and biophasic compartments for anti-mechanical pain effect, while there was no change at all for anti-thermal pain effect; (4) the difference in analgesia of a single dose of morphine across thermal and mechanical stimulus modalities was well reflected by the difference in the nonsteady-state and time-dependent PK-PD modeling, namely, the clockwise hysteresis loop model well represents the relationship of the time course between unconjugated/conjugated morphine concentration (both plasma and biophase) and anti-thermal pain effect, while the counter-clockwise hysteresis loop model well represents that between conjugated morphine concentration (mainly in biophase) and anti-mechanical pain effect. Taken together, the multiple PD-PK modeling is more useful in estimation and prediction of onset, magnitude and time courses of concentration-multiple pharmacological effects of morphine than simple PK or PD models, and establishment of various multiple PD-PK modeling might also be more useful in optimizing clinical use of existing drugs as well as new drugs for analgesia or treatment of other diseases.
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PMID:Nociceptive stimulus modality-related difference in pharmacokinetic-pharmacodynamic modeling of morphine in the rat. 1712 87


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