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At least 325 records · Page 18Linked to original sources

PubMed1995

C-fiber-evoked autonomic cardiovascular effects after injection of Piper betle inflorescence extracts.

Piper betle inflorescence extracts contain eugenol (6.2%) and safrole (78.9%). Intravenous injections of water extracts of P. betle inflorescence (PBE), eugenol, and safrole in rats induced hypotensive and bradycardiac effects, whereas both intraarterial and intrathecal injections of PBE, eugenol and safrole resulted in hypotensive and tachycardiac effects. Moreover, the effects of intravenous injections of PBE were reversed or inhibited by the pretreatment with bilateral vagotomy, atropine (1 mg/kg, i.p.) and capsaicin (100 mg/kg, s.c.). Effects of intraarterial injections of PBE on blood pressure were inhibited by the pretreatment with substance P (SP) antagonist (1 nmol, i.t.) and clonidine (2.5 micrograms, i.t.), while heart rate was only inhibited by the pretreatment with SP antagonist (1 nmol, i.t.). In addition, the tachycardia resulting from intrathecal injections of PBE was inhibited by pretreatment with propranolol (0.3 mg/kg, i.v.). Eugenol and safrole induced the same pattern on blood pressure and heart rate changes as PBE in rats after various treatments. This report suggests that acute administration of betel inflorescence extracts by different routes may activate C-fiber-evoked parasympathetic and sympathetic cardiovascular reflexes in rats.

Animals↗

PubMed1995

Sequential spinal epidural analgesia for pain relief in labour: an audit of 620 parturients.

This investigation was designed to evaluate sequential spinal epidural analgesia with a needle through needle technique for pain relief in labour. The spinal injection was made using a Becton Dickinson 29 gauge Quincke point needle. Bupivacaine 1 mg, sufentanil 5 microg and adrenaline 25 microg (2 ml) were injected intrathecally. Analgesia was maintained using bupivacaine 12.5 mg, sufentanil 10 microg and adrenaline 12.5 microg in a 10 ml bolus given through an epidural catheter in the epidural space. This dosage was also used for the test dose. Pain relief was obtained in less than ten minutes and lasted for a mean of 134 min. Of the 620 parturients in the investigation, 500 had a mean dose of 4.3 mg bupivacaine per hour. Hypotension and paresis were of no concern. Patient satisfaction was excellent, 85% of the parturients being very satisfied and 10% satisfied.

Journal Article↗

PubMed2004

Spinal neural cyclooxygenase-2 mediates pain caused in a rat model of lumbar disk herniation.

UNLABELLED: Application of nucleus pulposus to nerve root generates radicular pain. We demonstrated that these animals showed allodynia for 2 weeks, and cyclooxygenase-2 (COX-2) immunoreactivities were up-regulated in the spinal dorsal horn. COX-2 immunoreactivities were shown in neurons; however, they were not in astrocytes. Intrathecal administration of an antibody to COX-2 decreased allodynia. Our results suggest that COX-2 in spinal cord might be a target for treatment of patients with nerve root pain caused by lumbar disk herniation. PERSPECTIVE: Neural COX-2 might mediate nerve root pain in the spinal cord caused by lumbar disk herniation in rats.

Animals↗

PubMed2005

Increased cold allodynia following intrathecal N-methyl-D-aspartate in rats with a mononeuropathy.

NMDA receptors are involved in the modulation of neuropathic pain behavior and central sensitization. In vivo, this is mostly demonstrated by the use of specific antagonists such as MK801. Because studies evaluating the direct impact of spinal NMDA in neuropathic pain models are lacking, we performed a series of experiments to study the role of spinal NMDA injection on existing cold allodynia, as a measurement of neuropathic pain behavior in rodents. Intrathecal injection of NMDA resulted in an enhanced neuropathic pain behavior in CCI rats on a cold plate. The activity was present from a dose of 5 ng/rat onward and could selectively be reversed by intraperitoneal injections of doses of > or = 0.01 mg/kg MK801. These results support the regulatory role of NMDA receptors in the hypersensitivity to cold observed in neuropathic pain behavior in rodents.

Animals↗

PubMed2005

Effect of a selective GABA(B) receptor agonist baclofen on the mu-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects.

The management of excessive adverse effects of opioids is a major clinical problem. The present study was undertaken to investigate the effect of a selective gamma-aminobutyric acid (GABA)(B) receptor agonist baclofen on the mu-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects. Either morphine or fentanyl produced a dose-dependent antinociceptive effect in both ferrets using Randall-Selitto test and mice using tail-flick test. Under these conditions, pretreatment of baclofen produced an additive antinociception induced by morphine or fentanyl. Furthermore, the augmentation of antinociception induced by systemic administration of baclofen with morphine or fentanyl was completely abolished by either i.c.v. or i.t. pretreatment with the selective GABA(B) receptor antagonist CGP 35348 in mice. We next investigated the emetic response induced by mu-opioid receptor agonist in ferrets. Morphine at lower doses than that used for antinociceptive assay produced both retching and vomiting, whereas fentanyl failed to produce the retching and vomiting in ferrets. Here we reported for the first time that baclofen significantly suppressed the retching and vomiting induced by morphine, indicating the involvement of GABA(B) receptor in emetic control pathway. Furthermore, baclofen also inhibited place preference elicited morphine or fentanyl in rats. Taken together, these results suggest that co-administration of baclofen with mu-opioid receptor agonist produced a potentiation of antinociceptive effect, whereas an untoward effect was completely blocked.

Analgesics, Opioid↗

PubMed2004

Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat.

To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. Since suramin, an anti-parasitic and anti-cancer drug, which shares with the anti-retroviral nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular calcium, and a sensory neuropathy in humans, also produced mechanical hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular calcium. Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy.

Aminoquinolines↗

PubMed2005

Prodrug of proline analogue reduces hypoxic pulmonary hypertension in rats.

A polymeric prodrug of the proline analogue cis-4-hydroxy-l-proline (CHOP), poly(ethylene glycol)-lysine-CHOP or CHOP-PEG, prevents hypoxic pulmonary hypertension in rats by inhibiting collagen accumulation. A more potent prodrug was synthesized by increasing the loading of CHOP on the carrier from 14 to 100%. Pulmonary antihypertensive efficacy and pharmacokinetics are described in the rat hypoxia model. The antihypertensive effect of CHOP-PEG in rats exposed to 10% O2 for 7d showed approximately 2 x 10(2)-fold greater potency than monomeric CHOP. Routes of administration were compared to determine the lowest dose of CHOP-PEG that reduced right ventricular pressure approximately 50% vs. untreated hypoxic controls at 7d. Total doses required were: continuous s.c. via an osmotic minipump, 0.8 mg; single s.c., 10mg; single i.v., 40 mg; and single intratracheal 90 mg. Efficacy for at least 7d postdosing in pre-established pulmonary hypertension was shown. Using an ELISA-based assay, biphasic i.v. and stable s.c. pharmacokinetic profiles were observed 72 h after single injections and 7d after continuous s.c. infusion. Thus, this CHOP-PEG formulation prevents and reverses chronic hypoxic pulmonary hypertension in rats, is most effective when given by continuous s.c. infusion, and has favorable pharmacokinetic properties. Potent inhibitors of fibrosis appear to be promising agents in treating pulmonary hypertension and possibly other fibrosing diseases.

Animals↗

PubMed1997

Comparative antidepressant effects of intravenous and intrathecal thyrotropin-releasing hormone: confounding effects of tolerance and implications for therapeutics.

A significant amount of preclinical and human data indicate that thyrotropin-releasing hormone (TRH) has antidepressant effects. Although early studies showing these effects using intravenous TRH were not consistently replicated, it has been suggested that this could be explained by its poor blood-brain barrier penetration. For this reason we compared the antidepressant effect of intrathecal and intravenous TRH administered in a double-blind design to 2 treatment-refractory patients with bipolar II disorder. Each experienced a robust antidepressant response by both routes; subsequent open trials of intravenous TRH also were effective until apparent tolerance developed. Intrathecal TRH was readministered and both subjects again experienced robust antidepressant responses. These preliminary data suggest a differential mechanism of tolerance to the two routes of administration and raise the possibility that a subgroup of patients may be responsive to the antidepressant effects of TRH independent of its route of administration.

Affect↗

PubMed2002

Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury.

Nociceptin, acting through the opioid receptor-like 1 (ORL1) receptor, produces anti-nociception in several models of neuropathy. We examined the involvement of the ORL1 receptor system in the allodynia developed after sciatic nerve ligation. Allodynic rats were selected by the von Frey hair and treated intrathecally with nociceptin or morphine. The peptide induced dose-dependent anti-allodynic activities, while morphine was effective at the higher dose only. By the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, the two described ORL1 receptor isoforms were up-regulated in the allodynic animals, but unmodified in non-allodynic rats. Both short and long ORL1 receptor mRNA isoforms increased in the ipsilateral lumbar enlargement (by 50% and 100%, respectively), while 50% and 60% increases were found in the ipsilateral L5-L6 dorsal root ganglia, respectively. No significant changes were observed for either the nociceptin precursor or mu-opioid receptor expression. Thus, the ORL1 receptor system seems to regulate the mechano-allodynia that developed after nerve damage, suggesting its potential role in the treatment of neuropathic pain.

Analgesics, Opioid↗

PubMed2006

Roles of peripheral and central nicotinic receptors in the micturition reflex in rats.

PURPOSE: We investigated the effects of nicotinic acetylcholine receptor activation in the bladder and central nervous system on the micturition reflex in urethane anesthetized rats. MATERIALS AND METHODS: The effects of nicotinic acetylcholine receptor activation on bladder activity were examined during continuous infusion cystometrogram. Nicotine with or without the nicotinic acetylcholine receptor antagonist mecamylamine (Sigma Chemical Co., St. Louis, Missouri) was administered intravesically, intrathecally or intracerebroventricularly in normal or capsaicin pretreated rats. We also examined nicotine induced responses in dissociated bladder afferent neurons from L6 to S1 dorsal root ganglia that were sensitive to capsaicin using whole cell patch clamp recordings. RESULTS: Intravesical nicotine (1 to 10 mM) significantly decreased intercontraction intervals in dose dependent fashion. This excitatory effect was abolished by co-application of mecamylamine (3 mM) as well as by capsaicin pretreatment. On patch clamp recordings 300 muM nicotine evoked rapid inward currents that were antagonized by mecamylamine in capsaicin sensitive bladder afferent neurons. Intrathecal and intracerebroventricular administration of nicotine (10 mug) decreased and increase intercontraction intervals, respectively. Each effect was antagonized by mecamylamine (50 mug) administered intrathecally and intracerebroventricularly. The spinal excitatory effect was significantly inhibited by the N-methyl-D-aspartate receptor antagonist (+)-MK-801 hydrogen maleate (20 mug) given intrathecally or by capsaicin pretreatment, although the effects of capsaicin pretreatment were significantly smaller than those of (+)-MK-801 hydrogen maleate. CONCLUSIONS: These results indicate that nicotinic acetylcholine receptor activation in capsaicin sensitive C-fiber afferents in the bladder can induce detrusor overactivity. In the central nervous system nicotinic acetylcholine receptor activation in the spinal cord and brain has an excitatory and an inhibitory effect on the micturition reflex, respectively. In addition, the nicotine induced spinal excitatory effect may be mediated by the activation of glutamatergic mechanisms.

Administration, Intravesical↗

PubMed1996

Selective blockade of peripheral delta opioid agonist induced antinociception by intrathecal administration of delta receptor antisense oligodeoxynucleotide.

Previous studies have shown that intrathecal (i.t.) administration of antisense, but not mismatch, oligodeoxynucleotides (ODNs) to the cloned delta opioid receptor (DOR) can inhibit the antinociceptive actions of i.t. delta (delta), but not mu (mu) or kappa (kappa), opioid agonists. As a major portion of spinal opioid receptors are localized on the central terminals of the small afferent fibers, we hypothesized that the effects of antisense ODNs given i.t. might be the result of actions at the level of the cell body in the dorsal root ganglion (DRG). This possibility was investigated by assessing the antinociceptive actions of an i.t. or intrapaw (ipaw) administered mu (morphine), delta ([D-Ala2, Glu4]deltorphin) or kappa (CI977) opioid agonist in rats treated with i.t. saline or antisense or mismatch ODNs to the DOR (12.5 micrograms, twice-daily for 3 days). The opioid agonists produced significant antinociception in the 5% formalin-flinch test following either i.t. or ipaw administration. DOR antisense ODN treatment blocked the antinociceptive actions of both i.t. or ipaw [D-Ala2, Glu4]deltorphin without affecting the antinociceptive actions of i.t. or ipaw morphine or CI977. Radioligand binding studies with [3H]naltrindole (NTI), a delta selective antagonist, indicated an approximate 50% decrease in delta opioid receptors in the lumbar spinal cord following i.t. DOR antisense, but not mismatch, ODN treatment. DOR antisense or mismatch ODN treatment did not affect nu or kappa radioligand binding in lumbar spinal cord. These data suggest the possibility that peripheral proteins can be targeted with i.t. antisense ODNs providing significant opportunities for the exploration of the physiological and pathological significance of these substances.

Analgesics, Opioid↗

PubMed1998

The antinociceptive effect of moclobemide in mice is mediated by noradrenergic pathways.

Moclobemide is an antidepressant which affects the monoaminergic neurotransmitter system through a reversible inhibition of monoamine oxidase (MAO), preferentially type A. We examined the antinociceptive effects of moclobemide alone and in conjunction with specific opioid, adrenergic and serotonergic antagonists, using the mouse-tail flick test. Intraperitoneal moclobemide produced a dose-dependent antinociceptive effect with an ED50 of 69.1 mg/kg. Tests with selective antagonists yielded positive results only for yohimbine (P < 0.001), implying a noradrenergic mechanism of action in the moclobemide antinociceptive effect. This was confirmed by the coadministration of moclobemide with inactive doses of prototype agonists of the opioid, adrenergic and serotonergic systems. Only clonidine, an alpha2 agonist, significantly shifted (8-fold) the dose response curve of moclobemide. We conclude that there is a selective involvement of the alpha2 adrenergic pathways in the moclobemide-induced antinociceptive effect and a lesser involvement (if any) of the opioid, serotonergic and alpha1 adrenergic mechanisms. More research is needed to establish a possible role for moclobemide in pain management.

Analgesics↗

PubMed1997

Analgesic effects of amlodipine and its interaction with morphine and ketorolac-induced analgesia.

1. The antinociceptive effects of amlodipine, administered subcutaneously (s.c.), intracerebroventricularly (i.c.v.) and intrathecally (i.t.) were examined with the acetic acid writhing and tail-flick tests in mice. Amlodipine was also tested in combination with morphine and ketorolac. Isobolographic analyses were used to define the nature of functional interactions between amlodipine and morphine or ketorolac. 2. The s.c. (0.1, 1.25, 2.5, 5 and 10 mg/kg), i.c.v. (2.5, 5, 10 and 20 micrograms/mice) and i.t. (2.5, 5, 10 and 20 micrograms/mice) administration of amlodipine exhibited a dose-dependent antinociceptive effect in the writhing test but had no effect on the tail-flick latency. Isobolographic analyses revealed an additive interaction between amlodipine and morphine or ketorolac in the writhing test. 3. These results suggest that amlodipine induces antinociception and increases antinociceptive action of morphine and ketorolac, possibly through a decrease in cellular calcium availability.

Acetic Acid↗

PubMed1998

Subcutaneous morphine is superior to intrathecal morphine for pain control in a patient with hypernephroma.

This case report illustrates differences in analgesia quality and morphine consumption between an intrathecal infusion and the subcutaneous instillation of morphine in a cancer patient with hypernephroma. Superior analgesia was obtained with a 450 mg dose of subcutaneous morphine [i.e., visual analog scale (VAS) score 0/10] than with 10 mg intrathecal morphine/day administered at the thoracolumbar (twelfth dorsal vertebra) level (VAS score 2/10). If the instillation occurs at the lumbosacral level (between the last lumbar and the first sacral vertebra), a dosage of 70 mg morphine/day cannot induce the same pain relief as 450 mg subcutaneous morphine (VAS score 5/10 vs. 0/10). In some cancer patients, subcutaneous morphine offers superior pain control than intrathecal morphine.

Analgesics, Opioid↗

PubMed1996

Thromboembolic deterrent stockings fail to prevent hypotension associated with spinal anaesthesia for elective caesarean section.

This study was carried out to determine whether the use of thrombo-embolic deterrent (TED) stockings, in combination with an intravenous crystalloid preload, would prevent hypotension following spinal anaesthesia for caesarean section. Fifty parturients undergoing elective caesarean section under spinal anaesthesia were randomly allocated into two groups. TED stockings were applied to the study group 1 h before spinal anaesthesia but none were applied to the control group. Both groups received a crystalloid preload of 15 ml kg(-1) over 15 min before spinal injection. Significant hypotension, defined as an absolute value of systolic arterial pressure (SAP) of less than 90 mmHg and a decrease of more than 20% from baseline SAP was treated with 3 mg bolus of ephedrine as required. The difference in SAO between the two groups was not statistically significant. In the control group, 80% of parturients required ephedrine as opposed to 56% in the TED group; a difference that was also not statistically significant.

Clinical Trial↗

PubMed1996

Ketorolac and spinal morphine for postcesarean analgesia.

This study was designed to compare spinal morphine (SM), ketorolac (K), and a combination of the two drugs with respect to analgesic efficacy and side effects in postcesarean patients. Forty-eight parturients having bupivacaine spinal anesthesia for cesarean delivery randomly received in a double-blind manner either: SM: 0.1 mg or SM: 0.2 mg (but no K); SM: 0.1 mg plus K 60 mg intravenously (i.v.) one hour after spinal injection, and 30 mg i.v. every 6 h for three doses or i.v. K dosed as previously described (but no SM). Analgesia and side effects were evaluated during the first 20 h. Forty-eight women were studied. There were no significant differences in analgesia among the groups, although patients receiving SM: 0.1 mg tended to have less satisfactory intraoperative analgesia. Pruritus was common in all patients receiving SM whereas patients who received K had the lowest overall scores for severity of side effects. No serious complications occurred and all groups expressed similarly high satisfaction at the 24 h visit. We conclude that there is no advantage to combining SM and K, and that K provides satisfactory postcesarean analgesia with few side effects.

Clinical Trial↗

PubMed1996

Increases in vocalization and motor reflex thresholds generated by the intrathecal administration of serotonin or norepinephrine.

The capacity of serotonin and norepinephrine to elevate the thresholds of spinal motor reflexes (SMRs), vocalizations during shock (VDSs), and vocalization afterdischarges (VADs) when administered into the spinal subarachnoid space was evaluated. Both monoamines generated dose-dependent increases in the thresholds of all 3 responses. The minimum effective doses of serotonin and norepinephrine that elevated all 3 response thresholds were 40 micrograms and 1 microgram respectively. Monoamine-induced increases in response thresholds were reversed by the intrathecal administration of their corresponding receptor antagonists (phentolamine or methysergide). Threshold increases generated by serotonin were also partially reduced by phentolamine. These results indicate that dorsal horn neurons that underlie flexion reflex generation (SMR) and the rostral transmission of pain information (VDS and VAD) have similar thresholds of inhibition to spinopetal monoaminergic projections.

Afferent Pathways↗

PubMed2007

The synthetic TRH analogue taltirelin exerts modality-specific antinociceptive effects via distinct descending monoaminergic systems.

BACKGROUND AND PURPOSE: Exogenously administered thyrotropin-releasing hormone (TRH) is known to exert potent but short-acting centrally-mediated antinociceptive effects. We sought to investigate the mechanisms underlying these effects using the synthetic TRH analogue taltirelin, focusing on the descending monoaminergic systems in mice. EXPERIMENTAL APPROACH: The mice received systemic or local injections of taltirelin combined with either central noradrenaline (NA) or 5-hydroxytryptamine (5-HT) depletion by 6-hydroxydopamine (6-OHDA) or DL-p-chlorophenylalanine (PCPA), respectively, or blockade of their receptors. The degree of antinociception was determined using the tail flick and tail pressure tests. KEY RESULTS: Subcutaneously (s.c.) administered taltirelin exhibited dose-dependent antinociceptive effects in the tail flick and tail pressure tests. These effects appeared to be primarily supraspinally mediated, since intracerebroventricularly (i.c.v.) but not intrathecally (i.t.) injected taltirelin generated similar effects. Depletion of central NA abolished only the analgesic effect of taltirelin (s.c. and i.c.v.) on mechanical nociception. By contrast, depletion of central 5-HT abolished only its analgesic effect on thermal nociception. Intraperitoneal (i.p.) and i.t. injection of the alpha2-adrenoceptor antagonist yohimbine respectively reduced the analgesic effect of taltirelin (s.c. and i.c.v.) on mechanical nociception. By contrast, the 5-HT1A receptor antagonist WAY-100635 (i.p. and i.t.) reduced the effect of taltirelin (s.c. and i.c.v.) on thermal nociception. Neither the 5-HT2 receptor antagonist ketanserin nor the opioid receptor antagonist naloxone altered the antinociceptive effect of taltirelin. CONCLUSIONS AND IMPLICATIONS: These findings suggest that taltirelin activates the descending noradrenergic and serotonergic pain inhibitory systems, respectively, to exert its analgesic effects on mechanical and thermal nociception.

Adrenergic alpha-Antagonists↗