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PubMed1993

Inhibiting a spinal dynorphin A component enhances intrathecal morphine antinociception in mice.

Morphine given intracerebroventricularly releases spinal dynorphin A (Dyn) in mice. The present study was undertaken to determine whether morphine given intrathecally (IT) released Dyn. We demonstrated that the antinociceptive action of morphine was enhanced by procedures that are known to attenuate Dyn action. First, coadministration of the opiate antagonists, naloxone (5 fg), norbinaltorphimine (5 fg) or beta-funaltrexamine (0.25 ng) with IT morphine (0.15 microgram, 5 min) increased antinociceptive percentage maximum possible effect (%MPE) from 30% to 65%. Second, dynorphin antiserum (5 micrograms, 1 h, IT), which neutralizes Dyn action, enhanced morphine (0.2 microgram, 5 min, IT) action; MPE of 27% was increased to 60%. Third, production of desensitization to the antagonistic action of Dyn, IT, by pretreatment with morphine [10 mg/kg, 3 h, subcutaneously (SC)], or 2 micrograms, 3 h, IT) or Dyn (1 ng, 1 h, IT) increased the 30% MPE of IT morphine to 60%. Naloxone [1 ng/kg, intraperitoneally (IP)] enhanced IT morphine at a peak time of 20 min. Nalmefene [1 to 100 ng/kg, per os (PO)] enhanced IT morphine action. In conclusion, the present study showed that IT morphine putatively released spinal Dyn.

Analgesics↗
PubMed1987

Antagonism by nalmefene of systemic and intrathecal morphine-induced analgesia in mice.

Nalmefene is an orally active opiate antagonist structurally related to naloxone and naltrexone. In this study using two different strains of mice (Swiss Cox and ICR), the antagonist activity of nalmefene given subcutaneously (sc) was quantified by determination of the apparent pA2 values against the antinociceptive activity (tail flick and hot plate tests) of morphine given sc or intrathecally (lumbar spinal cord). The apparent pA2 values (constrained to a slope of -1) were 8.06 (7.79-8.33) in Swiss Cox mice and 7.81 (7.62-8.00) in ICR mice in the tail flick test with sc morphine. These values were larger than the corresponding value for naloxone in ICR mice, 7.35 (7.10-7.60). The hot plate test provided similar results: the apparent pA2 values for nalmefene with sc morphine were 8.14 (7.89-8.39) in Swiss Cox mice and 7.81 (7.65-7.97) in ICR mice, values which were different from naloxone 7.33 (7.23-7.42) in ICR mice. Apparent pA2 values for nalmefene with intrathecal morphine were not different from those for naloxone in the tail flick test. Thus, these sets of results suggest that it may be worthwhile to further determine whether systemic nalmefene might possibly possess an advantage over naloxone in antagonizing systemic side effects of morphine arising from local spinal morphine administration.

Analgesia↗
PubMed1991

Pain control with intrathecally and peridurally administered opioids and other drugs.

Sharp pain is conducted rapidly by myelinated delta A fibers and diffused pain slowly by nonmyelinated C fibers to pseudobipolar neurons in the posterior ganglion and from there to neurons located in the posterolateral horn of the spinal cord. From here on nociferous impulses are transmitted by excitatory peptides (e.g. substance P) or amino acids (e.g. glutamate, aspartate) through interconnecting neurons of the pain pathways, primarily on the contralateral side, to the brain stem and from there to the sensory cortex, where they are appreciated and acted upon. There are specific inhibitory receptors located on axon terminals, near to the release sites of the excitatory amino acids and peptides. Stimulation of these receptors by their appropriate ligands such as endogenous (e.g. enkephalis, endorphins) or exogenous opioids, clonidine, serotonin, somatostatin inhibits the release of excitatory neurotransmitters and relieves pain. There are at least 3 different opioid receptors, called mu-, kappa- and delta-receptors in the spinal cord. These can be differentiated from one another by their specific affinity toward different endogenous or exogenous opioids and the pure narcotic antagonist, naloxone. It appears that the nociferous impulses transmitted by parallel pathways equipped with different inhibitory receptors have to be integrated to produce pain sensation and partial inhibition of transmission in different pathways or complete inhibition in one of the pathways may relieve pain. In recent years the concept of "selective spinal analgesia" has been applied clinically for the relief of postoperative, obstetrical and chronic pain. At first it was expected that the intrathecal or peridural administration of morphine will produce analgesia without the side effects of systemically administered morphine. It soon became evident, however, that intrathecally and peridurally administered morphine after several hours of delay reaches the fourth ventricle and by stimulating mu-receptors may cause respiratory depression and other undesired effects (e.g. nausea, vomiting, pruritus). Several different approaches are being investigated for the production of selective spinal analgesia without side effects. They include: a. the use of more lipophilic, long-lasting opioids (e.g. lofentanil) which would be almost completely absorbed by the spinal cord and therefore would not reach the medullary centers; b. the development of opioids with specific affinity to kappa- and for delta- and little or no affinity to mu-receptors, primarily responsible for side effects; and c. combining lower doses of opioid agonists with alpha 2-adrenergic agonists (e.g. clonidine) or with somatostatin. It is conceivable that in the not-too-distant future, it will be possible to achieve through these measures, selective spinal analgesia without side effects.

Analgesics, Opioid↗
PubMed1991

Level of spinal anesthesia can be predicted by the cerebrospinal fluid pressure difference between full-flexed and non-full-flexed lateral position.

We studied whether cerebrospinal fluid pressure difference between full-flexed and non-full-flexed lateral position (dP) influences the spread of intrathecally (i.e., spinal) administered anesthetic solution (SSA). Forty-two women, 18-60 yr old, who underwent gynecologic surgery under spinal anesthesia were enrolled in the study. They were divided into two groups (group 1: less than 40 yr old, group 2: greater than or equal to 40 yr old). Before spinal anesthetic injection, we measured the pressure difference produced by postural change from the right lateral decubitus position (non-full-flexed) for needle insertion at the L2-3 interspace to a full-flexed lateral decubitus position with a spinal needle in place. After they returned to the non-full-flexed lateral position, 14 mg of plain tetracaine in 10% dextrose solution (2.8 mL) was injected intrathecally in each patient. Pressure differences had a significant correlation with the cephalad levels of spinal anesthesia in each group; the larger pressure difference was associated with a larger SSA. The relationship was stronger in the younger group (correlation coefficients, 0.82 and 0.63; P-values less than 0.01 in groups 1 and 2, respectively). Three patients in group 1 developed T-2 anesthesia, whereas no one in group 2 did (P less than 0.01), and their pressure difference values ranged from 12 to 16 cm H2O, substantially larger than those of the other patients in group 1. Five patients in group 2 developed T-3 anesthesia, whereas no patient in group 1 (P less than 0.01) did, and their pressure differences were not essentially larger than those of the rest in the same group. The authors conclude that pressure differences correlated with the SSA, although the mechanism remains to be clarified. It seems possible to predict which patient in the younger patient group may develop unintentional high spinal anesthesia (T-3 or higher) by measuring pressure differences.

Adult↗
PubMed1998

A transient neurological deficit following intrathecal injection of 1% hyperbaric bupivacaine for unilateral spinal anaesthesia.

We describe a case of transient neurological deficit that occurred after unilateral spinal anaesthesia with 8 mg of 1% hyperbaric bupivacaine slowly injected through a 25-gauge pencil-point spinal needle. The surgery and anaesthesia were uneventful, but 3 days after surgery, the patient reported an area of hypoaesthesia over L3-L4 dermatomes of the leg which had been operated on (loss of pinprick sensation) without reduction in muscular strength. Sensation in this area returned to normal over the following 2 weeks. Prospective multicentre studies with a large population and a long follow-up should be performed in order to evaluate the incidence of this unusual side effect. However, we suggest that a low solution concentration should be preferred for unilateral spinal anaesthesia with a hyperbaric anaesthetic solution (if pencil-point needle and slow injection rate are employed), in order to minimize the risk of a localized high peak anaesthetic concentration, which might lead to a transient neurological deficit.

Adult↗
PubMedDate not supplied

Sedation after spinal anesthesia in elderly patients: a preliminary observational study with the PSA-4000.

PURPOSE: Neuraxial blockade is known to have a sedative effect, decreasing the need for inhalational and iv anesthetic agents. The purpose of the present study was to quantify the sedative effect of spinal anesthesia and to determine the time of maximum sedation. METHODS: This is an observational study in which 20 unsedated patients were scheduled to undergo urologic and orthopedic surgeries under spinal anesthesia. Patients with pre-existing neurological conditions or receiving psychotropic medications were excluded from the study. All received 1.5 mL (11.25 mg) of hyperbaric bupivacaine 0.75% intrathecally. No sedative or narcotic was administered intravenously or intrathecally. The Patient State Analyzer, (PSA-4000) was used to monitor sedation along with Observer's Assessment of Alertness and Sedation (OAA/S) scores every five minutes. Differences in patient state index (PSI) and OAA/S scores are expressed as median and range and were evaluated by Wilcoxon's signed rank test for non-parametric data; P < 0.05 was considered significant. PSI, OAA/S and time at lowest score are expressed as median(range). RESULTS: PSI scores decreased from baseline 99 (96-99) to 78 (56-87) at 35(14.5-54) min into the spinal anesthetic (P < 0.05). OAA/S scores decreased from baseline 5 to 4 (range 3-5) at the time of the lowest PSI scores (P < 0.05). CONCLUSIONS: In this elderly patient population, spinal anesthesia induced changes in the processed electroencephalogram with reduction in PSI and OAA/S scores. The reduction in afferent input to the reticular activating system could possibly explain the sedation that has been observed and the reduction in the PSA scores.

Aged↗
PubMedDate not supplied

Automated intermittent epidural boluses improve analgesia induced by intrathecal fentanyl during labour.

PURPOSE: We compared the efficacy of epidural continual intermittent boluses (CIB) with a continuous epidural infusion (CEI) in prolonging labour analgesia induced by the combined spinal epidural (CSE) technique. METHODS: CSE was instituted in 42 nulliparous parturients at the L3 to 4 level with intrathecal (IT) fentanyl 25 micro g followed by an epidural test dose of 3 mL of 1.5% lidocaine. These parturients were then randomly assigned to receive either epidural CIB (n = 21) or CEI (n = 21) with 0.1% ropivacaine and fentanyl 2 micro g x mL(-1). For the CIB, 5 mL boluses were given hourly, with the first bolus 30 min postinduction. CEI at the rate of 5 mL.hr(-1) was initiated in the minute after CSE. The duration of analgesia, pain score, degree of sensorimotor block were compared. RESULTS: From Kaplan Meier survival analysis, the duration of analgesia was significantly longer in CIB (mean survival time 239 +/- SD 24 min vs 181 +/- 17, P < 0.05 using log rank test). During the first three hours postblock, the median sensory block to cold was higher in CIB (P < 0.05, Mann U Whitney test) but no difference in blood pressure was detected [P > 0.05, repeated measure analysis of variance (RMANOVA)]. The serial pain scores were lower in the CIB (P < 0.05, RMANOVA). CONCLUSION: CIB prolonged the duration and improved the quality of analgesia. CIB could have resulted in an improved spread of analgesics in the epidural space or encouraged a direct passage of infusate into the IT space. This could have also rendered a higher sensory block to cold in the CIB group. CIB is a good alternative to CEI for the maintenance of epidural analgesia after CSE.

Amides↗
PubMed1995

Altered N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine is mediated by sigma activity.

The present study was designed to determine whether the increase in N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord, unmasked by naloxone in morphine-pretreated mice, is mediated by sigma receptor activity. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.) except when NMDA was injected together with 0.1 micrograms of naloxone. This excitatory effect of morphine on NMDA-induced behaviors, unmasked in the presence of naloxone was prevented but not reversed by haloperidol, a sigma ligand and dopamine antagonist, but not by an equivalent dose of spiperone, a dopamine antagonist. Sigma activity also appeared to contribute to morphine withdrawal jumping in mice as haloperidol inhibited naloxone-induced jumping while spiperone did not. Together these data indicate that naloxone unmasks an action of morphine on NMDA and during acute withdrawal, and these effects are each brought about by mechanisms involving sigma receptor activity.

Animals↗
PubMed1994

Increased N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine does not mediate opioid withdrawal.

N-Methyl-D-aspartate (NMDA) receptors have been proposed to play a role in opioid tolerance and dependence. The present study was designed to determine whether the increased NMDA activity in the spinal cord, unmasked by naloxone in morphine-pretreated mice, reflects activity leading to opioid withdrawal. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.), but enhanced following morphine when naloxone was injected together with NMDA. Although injected at doses that inhibited NMDA activity, the excitatory effects of morphine on NMDA-induced behaviors were prevented by dizocilpine (MK-801), a phencyclidine (PCP) ligand, but not by 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1 phosphonic acid (CPP), a competitive NMDA antagonist. MK-801 also inhibited naloxone-induced withdrawal jumping, however, just as CPP failed to affect morphine-induced changes in MMDA-induced behaviors, CPP also failed to inhibit withdrawal jumping. Together these data indicated that withdrawal from acute opioid dependence correlates with, but is not mediated by enhanced NMDA activity.

Analysis of Variance↗
PubMed1988

The pattern of pyridoxine-induced lesion: difference between the high and the low toxic level.

A fundamental prerequisite for the design of neurotoxicological safety studies is the determination of the target areas in the nervous system which are specific for particular kinds of toxicants. The target areas should be identified in special "lesion-pattern-finding" experiments. The pyridoxine-induced lesion is a prototype of the pattern characteristic of a peripheral, primary sensory neuropathy. Depending on the conditions of treatment such as the dosage level and the timing of examination, the structural changes may be more obvious either in the proximal or the distal portion of the neuron, while the functional signs may vary from severe sensory paralysis to quite unremarkable behavior.

Animals↗
PubMed2000

Intrathecal N-methyl-D-aspartate (NMDA) induces paradoxical analgesia in the tail-flick test in rats.

The intrathecal (IT) administration of NMDA in rodents has usually been reported to produce hyperalgesic reactions, although some articles describe that spinal NMDA can lead to analgesia. We show here that the nociceptive behavior (biting, scratching, licking; BSL) observed after NMDA injection (1-8 microg/rat; IT) is followed by a long period of increased tail-flick latencies, not longer detected 24 h after NMDA administration. The NMDA-receptor antagonist CPP (10-100 ng/rat; IT) blocked the BSL behavior induced by NMDA. In the tail-flick test, this antagonist induced analgesia by itself, and was able, at 30 ng/rat, to prevent the NMDA-mediated analgesia. The implication of opiate mechanisms was discarded since naloxone (3 and 10 mg/kg; IP) did not antagonize NMDA-induced analgesia. Finally, the involvement of the intracellular calcium binding protein calmodulin was assessed. The calmodulin inhibitor, calmidazolium (30-300 microg/rat; IT) only blocked the excitatory effect (BSL) without modifying the tail-flick analgesia produced by NMDA (4 microg). These results show that a single intrathecal administration of NMDA sequentially induces both nociceptive and antinociceptive, nonopiate responses in rats.

Analgesics, Non-Narcotic↗
PubMed2003

Polyethylene glycol modified polyethylenimine for improved CNS gene transfer: effects of PEGylation extent.

Poor solubility of polycation complexes with DNA is one drawback for their in vivo use as gene delivery systems. PEGylation often can improve the solubility of the complexes, minimize their aggregation and reduce their interaction with proteins in the physiological fluid. We investigated in vivo application of polyethylene glycol (PEG) modified polyethylenimine (PEI) for gene expression in the central nervous system. Varied numbers of linear PEG (2 kDa) were grafted to branched PEI (25 kDa) from the average number of PEG per one PEI macromolecule at 1-14.5. While higher degrees of PEG grafting did not improve gene expression, a PEI conjugate with one segment of PEG was able to mediate transgene expression in the spinal cord up to 11-fold higher than PEI homopolymer after intrathecal administration of its DNA complexes into the lumbar spinal cord subarachnoid space. Improved gene expression with this conjugate was observed as well in the brain after the lumbar injection. As assessed in in vitro studies, the PEI conjugate with a low degree of PEG grafting was able to reduce the size of polymer DNA complexes, prevent the aggregation of complexes, decrease the interactions of the complexes with serum proteins, counter the inhibition of serum to gene transfer, and enhance transfection efficiency, although not significant in affecting complex formation and reducing in vitro cell toxicity of PEI. The study provides the in vivo evidence that an appropriate degree of PEG modification is decisive in improving gene transfer mediated by PEGylated polymers.

Animals↗
PubMed1990

[Intrathecal and epidural administration of alpha adrenergic receptor agonists].

Alpha-agonists are frequently added to local anaesthetic agents to prolong the duration of spinal or extradural anaesthesia. Adrenaline and phenylephrine have been employed most commonly for this purpose. Recent controlled studies indicated that the alpha-adrenoceptor agonist clonidine, when administered spinally, has a dose-dependent antinociceptive effect. Clonidine seems to be as effective as adrenaline to prolong the duration of local anaesthetic blocks and is useful to decrease the incidence of tourniquet pain under spinal anaesthesia. As they improve the intensity and duration of opioid analgesia, intraspinal alpha-agonists have also a synergic analgesic effect with spinal opioids. Alpha-agonist effects are due: 1) to an activation of the post and/or presynaptic alpha 2-adrenoceptors in the substantia gelatinosa of the spinal cord, 2) to a local vasoconstriction by stimulating vascular smooth muscle alpha-receptors which decrease the rate of absorption of local anaesthetics from the subarachnoid or extradural space, 3) to a co-activation of the spinal opioid and alpha-adrenergic receptors at the spinal cord level. However, spinally administered alpha-agonists have side effects, which include vasoconstriction in the spinal cord, hypotension, bradycardia or tachycardia, somnolence and respiratory depression. To minimize such complications, great care may be needed, which is described in this review, assessing the minimal required amount of alpha-agonists and effective clinical monitoring. The development of this technique in the management of subarachnoid and extradural anaesthesia and of chronic pain is discussed.

Adrenergic alpha-Agonists↗
PubMed1999

Intrathecal morphine for coronary artery bypass graft procedure and early extubation revisited.

OBJECTIVE: To determine the dose of intrathecal (IT) morphine (along with the intraoperative baseline anesthetic) that provides significant analgesia yet does not delay extubation in the immediate postoperative period in patients undergoing cardiac surgery and early extubation. DESIGN: Prospective, randomized, double-blinded, placebo-controlled clinical study. SETTING: Single university hospital. PARTICIPANTS: Forty patients undergoing elective coronary artery bypass graft procedure and early extubation. INTERVENTIONS: Twenty patients received 10 microg/kg of IT morphine, and 20 patients received IT placebo. Perioperative anesthetic management was standardized and included postoperative patient-controlled morphine analgesia. MAIN RESULTS: Of the patients tracheally extubated during the immediate postoperative period, mean time to extubation was similar in patients who received IT morphine (6.8+/-2.8 h) or IT placebo (6.5+/-3.2 h). Four patients who received IT morphine had extubation substantially delayed because of prolonged ventilatory depression. There was no difference between groups in postoperative patient-controlled morphine analgesia use. CONCLUSION: Even when used in conjunction with an intraoperative baseline anesthetic that allows early extubation, IT morphine (10 microg/kg) was unable to provide substantial postoperative analgesia. The risks of using IT morphine in patients undergoing cardiac surgery and early extubation may outweigh the potential benefits.

Aged↗
PubMed2000

Efficacy of intrathecal neostigmine for the relief of postinguinal hemiorrhaphy pain.

BACKGROUND: Intrathecal administration of various doses of neostigmine has been reported to produce analgesia without neurotoxicity in both animal and human studies. The present study was undertaken to evaluate the efficacy and safety of intrathecal neostigmine for the relief of pain for patients having undergone inguinal herniorrhaphy surgery. METHODS: Sixty men scheduled for elective inguinal herniorrhaphy with spinal anaesthesia were randomly allocated to three groups: group I (n=20) received intrathecal (IT) tetracaine 15 mg, group II (n=20) received IT tetracaine 15 mg+ neostigmine 50 microg, and group III (n=20) received IT tetracaine 15 mg+neostigmine 100 microg. The onset of anaesthesia, duration of analgesia, time to use of first rescue analgesics, the overall 24 h VAS pain scores and the incidence of adverse effects were recorded for 24 h postdrug administration. RESULTS: Onset of anaesthesia (time to T6 sensory block) was significantly faster for group II and III patients compared with group I patients. Motor block (time to lift leg) was greatly prolonged for group III patients, with an average of 6.4 h, compared with 4.1 h for group II patients. Group III patients also showed a later onset of postsurgical pain, lower overall 24-h VAS pain score and prolonged time to first rescue analgesics than did group II patients. There was a significantly greater incidence of adverse effects associated with IT neostigmine, especially nausea and vomiting. CONCLUSION: Our study showed that intrathecal neostigmine at 50 pg or 100 microg enhanced the onset of tetracaine anaesthesia and provided analgesia lasting for 6-9 h, although increased incidences of prolonged motor blockade and nausea or vomiting were noted.

Adult↗
PubMed2003

Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain.

1. In an attempt to clarify whether glial cell line-derived neurotrophic factor (GDNF), a survival factor for subpopulations of primary afferent neurons, is involved in the states of neuropathic pain, we observed changes in the expressions of GDNF and its signal-transducing receptor Ret after nerve injury in two rat models of neuropathic pain. 2. In the rats treated with sciatic nerve ligation (chronic constrictive injury (CCI) model) or spinal nerve ligation at L5 (SNL model), the thresholds of paw withdrawal in response to mechanical or heat stimuli began to decrease on the injured side within the first week after the operation and the decreases in the thresholds persisted for more than 2 weeks. 3. In CCI-treated rats, the GDNF contents in L4 and L5 dorsal root ganglia (DRGs) on the injured side were markedly decreased at day 7 after the operation and stayed at low levels at day 14. In SNL-treated rats, comparable reductions of GDNF levels in L4 and L5 DRGs on the injured side were observed at 14 postoperative days. 4. Significant decreases of the percentages of DRG neurons expressing Ret were also observed at L4 DRGs in CCI-treated rats at 7 and 14 postoperative days and in SNL-treated rats at 14 days. 5. In CCI- or SNL-treated rats, continuous intrathecal administration of GDNF (12 microg day-1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. 6. The present results suggested that the dysfunction of GDNF signaling in the nociceptive afferent system may contribute to the development and/or maintenance of neuropathic pain states.

Animals↗