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)

Adrenal medullary chromaffin cells produce high levels of endogenous opioid peptides. Recent data suggest that transplantation injected locally into the spinal subarachnoid space reduced intractable malignant pain. In order to determine the feasibility, the efficacy and the risks of using adrenal medullary tissue for control of irreducible pain, we have developed a transplantation protocol on cancer pain patients selected when they required chronic intrathecal injection of morphine and progressively increasing doses to maintain the level of analgesic effects. At the present time, our clinical trial involves 8 patients. We report here our initial results (mean follow-up: 5 months). The various data collected before and after the intrathecal administration of chromaffin cells included: 1) Pain evaluation over time, with concomitant narcotic intake, 2) CSF sampling through an implanted access port to determine the following biological parameters: biochemical assay for opioid peptides, cell count and phenotyping of lymphocytes, 3) peripheral blood samples for lymphocyte typing. The results confirm the efficacy of adrenal medullary transplantation into spinal CSF for controlling irreducible cancer pain. Complementary intrathecal and oral morphine were totally stopped in 2 cases and stabilized in 5 others. It seems essential to have an important volume of grafted tissue to achieve analgesia with high levels of metenkephalin in CSF. A progressive decrease in metenkephalin release was observed from 2 to 4 months after the transplantation. Two patients with a long-term follow-up (8 and 12 months) needed another intrathecal chromaffin cell graft.
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PMID:Transplantation of human chromaffin cells for control of intractable cancer pain. 874 93

[D-Penicillamine2,5] enkephalin (DPDPE) is an enzymatically stable, delta-opioid receptor-selective peptide, which produces analgesia when given intracerebroventricularly. However, because only modest analgesic effects were seen after subcutaneous administration of DPDPE, it has been inferred that it does not cross the blood-brain barrier well. In this present study, a vascular brain perfusion technique in anesthetized rats was used to measure directly whether [3H]DPDPE could cross the blood-brain and/or the blood-CSF barriers. The results indicated that the brain uptake of [3H]DPDPE was significantly greater than that of [14C]sucrose, a vascular marker (p < 0.01), and than that of [3H]DPDPE into the CSF (p < 0.01). Furthermore, HPLC analysis confirmed the integrity of the 3H to DPDPE and demonstrated that intact [3H]DPDPE entered the brain. Although 1 mM leucine-enkephalin failed to inhibit uptake of [3H]DPDPE, unlabeled DPDPE (100 microM) caused a significant inhibition of the brain uptake (p < 0.01) but not the CSF uptake of [3H]DPDPE. These data provide evidence that intact [3H]DPDPE enters the CNS of anesthetized rats by saturable and nonsaturable mechanisms. In addition, the saturable mechanism is likely to be found at the blood-brain barrier, with the blood-CSF barrier playing only a minor role in the brain uptake of this peptide.
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PMID:Passage of a delta-opioid receptor selective enkephalin, [D-penicillamine2,5] enkephalin, across the blood-brain and the blood-cerebrospinal fluid barriers. 876 96

Epidural administration of combinations of opioids and a local anaesthetic provides prompt and effective analgesia and is increasingly used in paediatric anaesthesia. However, respiratory depression by rostral spread of opioid in the CSF is by far the greatest concern after epidural morphine. An infant of three months of age underwent portoenterostomy (Kasai's operation) for extrahepatic biliary duct atresia. A median approach at the L3-L4 epidural interspace was used and a dose of 1 ml.kg-1 of 0.125% bupivacaine with adrenaline 1:400000 mixed with 50 micrograms.kg-1 morphine was injected using a 19 gauge Tuohy needle. Six h after epidural morphine, the infant developed respiratory depression with an increase in drowsiness, miosis and decreased respiratory rate. Low arterial saturation (SpO2) was detected by pulse oximetry and confirmed by blood gas analysis. An intravenous bolus of 5 micrograms.kg-1 naloxone followed by a 3-h infusion of 2 micrograms.kg-1.h-1 resulted in complete reversal of signs and symptoms of respiratory depression. Epidural opioids should be limited to paediatric patients admitted to specialized recovery units for the first postoperative day.
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PMID:Respiratory depression following epidural morphine in an infant of three months of age. 948 11

1. The responses of wide dynamic range spinal dorsal horn neurones to noxious mechanical stimulation of the ankle or knee joint were tested before and after spinal administration of the non-selective cyclooxygenase (COX) inhibitors, indomethacin and meclofenamic acid. Neither of these drugs altered the responses of these neurones to noxious mechanical stimulation. 2. Wind-up of a spinal nociceptive reflex evoked by electrical stimulation of the sural nerve at C-fibre strength was dose-dependently inhibited by intravenous administration of indomethacin, a non-selective COX inhibitor, and SC58125, a selective COX-2 inhibitor. Intrathecal administration of indomethacin also reduced the wind-up of this nociceptive reflex. 3. Western blot analysis of proteins extracted from normal rat spinal cord revealed the presence of both cyclo-oxygenase (COX)-1 and COX-2 proteins. 4. Immunocytochemistry of sections of normal rat spinal cord with specific COX-1 antiserum revealed little specific COX-1-like immunoreactivity in the grey matter. With the same antiserum, intense COX-1-like immunoreactivity was observed in the cytoplasm, nuclear membrane and axonal processes of small to medium sized (< 1000 microns2) dorsal root ganglion (DRG) cell bodies. 5. Immunocytochemistry of sections of normal rat spinal cord incubated with specific COX-2 antiserum showed intense COX-2-like immunoreactivity (COX-2-li) in the superficial dorsal horn of the spinal cord (laminae I and II) and around the central canal (lamina X). COX-2-li was also observed in some neurones in deep dorsal horn and in individual motor neurones in ventral horn. COX-2-li was not observed in the cell bodies of DRG. 6. Superfusion of the lumbar spinal cord of normal rats with artificial CSF and subsequent radioimmunoassay revealed the presence of prostaglandin D2 (PGD2) < PGE2, but not PGI2 (determined by measurement of the stable metabolite, 6-keto-PGF1 alpha) or PGF2 alpha. 7. These data suggest that eicosanoids synthesized by an active COX pathway in the spinal cord of normal animals may contribute to nociceptive processing, but only when the spinal cord neurones are rendered hyperexcitable following C-fibre stimulation. Selective inhibition of one or both of the COX isoforms in normal animals may represent a novel target for spinal analgesia.
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PMID:Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. 942 3

A number of pre-clinical studies have demonstrated the value of adrenal medullary allografts in the management of chronic pain. The present longitudinal survey studied 15 patients transplanted for intractable cancer pain after failure of systemic opioids due to the persistence of undesirable side-effects. Before inclusion, all the patients had their pain controlled by daily intrathecal (I-Th) morphine administration. The main evaluation criteria of analgesic activity of the chromaffin cell allograft was the complementary requirement of analgesics and in particular the consumption of I-Th morphine required to maintain effective pain control. Out of the 12 patients who profited from enhanced analgesia with long-term follow-up (average 4.5 months), five no longer required the I-Th morphine (with prolonged interruption of systemic opioids as well), two durably decreased I-Th morphine intake and five were stabilized until the end of their follow-up. Durable decline and stabilization were interpreted as indicative of analgesic activity by comparison with the usual dose escalation observed during disease progression. In most cases, we noted a relationship between analgesic responses and CSF met-enkephalin levels. The results of this phase II open study demonstrate the feasibility and the safety of this approach using chromaffin cell grafts for long-term relief of intractable cancer pain. However, while analgesic efficacy was indicated by the reduction or stabilization in complementary opioid intake, these observations will need to be confirmed in a controlled trial in a larger series of patients.
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PMID:Human chromaffin cell graft into the CSF for cancer pain management: a prospective phase II clinical study. 1086 42

There is conflicting evidence regarding the issue of whether NMDA receptors in the basolateral amygdalar complex (BLA) are critically involved in the expression of conditioned fear. This matter was addressed by infusing the rat BLA with d,l-2-amino-5-phosphonovaleric acid (APV), a competitive NMDA receptor antagonist. APV infusion into the BLA was reported to block the expression of conditioned fear when measured by freezing but not when measured by fear-potentiated startle response to a loud noise. To examine this issue further, here we used multiple indices of conditioned fear, including analgesia, 22 kHz ultrasonic vocalization (USV), defecation, and freezing. Rats with bilateral BLA cannula implants underwent fear conditioning consisting of 10 tone-footshock pairings. Before context and tone fear-retention tests, animals received intra-BLA infusions with APV (2.5 microg/side) or artificial CSF. Both tone and context tests demonstrated that the expression of conditioned freezing, USV, defecation, and analgesia were significantly impaired by intra-amygdalar infusions of APV. In a second set of experiments, intra-BLA infusions of APV markedly impaired the normal expression of postshock fear responses during training, as measured by freezing, USV, and defecation. Immediate postshock fear expression was predictive of subsequent fear retention to the tone and context when the animals were not infused. These results are consistent with the hypothesis that amygdalar NMDA receptors participate in normal synaptic transmission and therefore the overall functioning of the amygdala.
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PMID:Amygdalar nmda receptors are critical for the expression of multiple conditioned fear responses. 1135

Methylnaltrexone (MNTX) is the first peripheral opioid receptor antagonist used in man to treat acute and chronic opiate-mediated side-effects. We describe in a rabbit model the pharmacokinetics of epidurally administered MNTX 0.66 mg kg(-1), and we tested the hypothesis that epidurally administered MNTX does not penetrate the dura into the subarachnoid space. There were minimal concentrations of MNTX (40 ng ml(-1)) detected in the CSF at 10 and 20 min and none thereafter in comparison with the high serum levels. The serum drug concentration-time profile fitted a two-compartment pharmacokinetic model. Further studies are warranted as epidurally administered MNTX may have the potential to reverse epidural opioid-mediated side-effects whilst preserving analgesia.
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PMID:Pharmacokinetic profile of epidurally administered methylnaltrexone, a novel peripheral opioid antagonist in a rabbit model. 1157 86

The incidence of epidural needle-induced post-dural puncture headache (PDPH) in parturients following dural puncture with a large bore (18-gauge) needle has been reported to range 76-85%. We describe seven cases in which the performance of epidural anesthesia in parturients was complicated by an unintentional dural puncture with an 18-gauge epidural needle. In all seven cases, the unintentional dural puncture was followed by (i) injection of the CSF in the glass syringe back into the subarachnoid space through the epidural needle, (ii) insertion of a epidural catheter into the subarachnoid space (now referred to as an intrathecal catheter), (iii) injection of a small amount of preservative free saline (3-5 ml) into the subarachnoid space through the intrathecal catheter, (iv) administration of bolus and then continuous intrathecal labor analgesia through the intrathecal catheter and then (v) leaving the intrathecal catheter in-situ for a total of 12-20 h. PDPH occurred in only one of these cases (14%).
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PMID:Decrease in the incidence of post-dural puncture headache: maintaining CSF volume. 1524 44

Back pain, chemical backache, PDPH, and neurologic deficit all may be reported after regional anesthesia for childbirth. Back pain is common during pregnancy, but epidural analgesia during labor does not increase the incidence of long-term back pain. Chemical backache caused by 2-chloroprocaine is probably a result of hypocalcemic tetany of paraspinous muscles. The mechanism is presumed to be chelation of calcium by sodium bisulfite, an antioxidant present in nesacaine-MPF. PDPH after dural puncture is caused by leakage of CSF, which causes cerebral hypotension. Cerebral hypotension leads to traction on pain-sensitive intracranial structures and cerebral vasodilation. Initial therapy includes hydration, caffeine, and sumatriptan. EBP is the most effective treatment in severe PDPH. If the first EBP fails, a second blood patch can be performed. Neurologic deficits after regional anesthesia are rare. Meticulous technique and vigilance are the keystones in avoiding major neurologic complications of regional anesthesia. Rapid diagnosis and appropriate treatment are essential to optimize a successful outcome if complications do develop.
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PMID:Backache, headache, and neurologic deficit after regional anesthesia. 1269 33

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


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