Duration Of Antinociception Research Articles

A Comparison of Two Epidural ??2???Agonists, Guanfacine and Clonidine, in Regard to Duration of Antinociception, and Ventilatory and Hemodynamic Effects in Goats

Epidural clonidine produces analgesia in humans with acute and chronic pain. Its use is limited because of short-lasting analgesia, hemodynamic depression, sedation, and respiratory depression. Intrathecal guanfacine has a longer duration of action than intrathecal clonidine. The present study compares these two drugs administered epidurally. Pulmonary artery, carotid artery, and epidural catheters were inserted into five goats. Each animal received guanfacine 5 mg/10 mL, clonidine 750 micrograms/10 mL, or a 10-mL saline control solution on separate occasions. Antinociception (tested via a point pressure stimulation device), arterial blood pressure, heart rate, cardiac output, pulmonary capillary wedge pressure, and arterial and mixed venous blood gases were measured every 30 min for 8 h. Guanfacine produced a longer duration of antinociception (guanfacine = 8 h vs clonidine = 5.5 h). Increases in PaCO2 were more pronounced in the clonidine group. There were no marked hemodynamic differences between the two drugs. Pretreatment with epidural idazoxan, an alpha 2-antagonist, blocked the antinociceptive effects of guanfacine. Because of a longer duration of action and less respiratory depression, epidural guanfacine may be superior for postoperative analgesia and chronic pain syndromes.

Environmental modulation of behavioral tolerance in spinal rats

We previously reported that the antinociceptive effect of morphine on the thermal tail withdrawal reflex (tail flick, TF) was reduced in rats that had practiced the TF response prior to morphine administration. This phenomenon, termed behavioral tolerance, was observed even when rats were spinally transected following the TF tests. The present experiments were conducted to determine whether such retention of behavioral tolerance after spinal transection was dependent on prior experience with the TF procedure, or whether other nociceptive pretreatments would also reduce opiate antinociception on the TF test in spinal rats. Separate groups of rats were pretreated with either nociceptive thermal TF or Hot Plate (HP), or mechanical Tail Pinch (TP) stimuli, as well as non-nociceptive exposure to the experimental context (Habituation) or No Pretreatment. Approximately half of the rats were spinally transected after their respective pretreatment, while the other half were left intact. When Intact rats were subsequently tested on the TF at 30, 60, 120 and 180 min after morphine administration, only the TF pretreated group was tolerant, relative to the Non-pretreated control group. However, this was a transient effect, and was only significant at the first, 30-min test; there was no difference among the groups in the total duration of antinociception across all the time points. When spinal rats were tested after morphine administration, there was also an overall significant difference among the groups at 30 min. In this case, the differences were maintained across all time points. All three nociceptive pretreatments (TF, HP and TP) significantly reduced the total duration of opiate antinociception in acute spinal rats, relative to the Non-pretreatment condition, whereas the Habituation treatment did not. These data reveal a differential effect of behavioral pretreatment on morphine-induced antinociception in Intact vs. Spinal rats. In Intact rats, behavioral tolerance on the TF test was transient and only observed in animals that had prior experience with the TF procedure. In contrast, when rats were spinally transected after nociceptive pretreatment, behavioral tolerance on the TF test was maintained throughout the test session and was observed in all of the nociceptive pretreatment groups. These data indicate first that nociceptive stimulation can produce a persistent change in the spinal cord which significantly influences spinal reflex function and second that when the neuraxis is intact, the effect of such stimulation may be modulated by descending supraspinal input.

Dose-Response of Intravenous Butorphanol to Increase Visceral Nociceptive Threshold in Dogs

This study was designed to determine the effective analgesic dose of butorphanol administered intravenously to obtund visceral nociception, as well as to determine duration of this effect. Additionally, cardiovascular changes and sedative effects were defined. Eight healthy dogs were each given five doses of butorphanol (0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg) plus a sterile water placebo intravenously in a randomized blinded format. Antinociception was assessed using an inflatable Silastic balloon inserted into the colon. Blood pressures and pulse rates were measured with a noninvasive monitor. The greatest efficacy and longest duration of antinociception were produced by 0.4 mg/kg of butorphanol, with a duration of 38 +/- 9 min. Arterial blood pressure and pulse rate did not vary at antinociceptive doses. Mild sedation was observed at all doses, which generally lasted longer than the antinociceptive effects. These data suggest that butorphanol can be given alone intravenously to provide visceral antinociception lasting 30-45 min without significant side effects.

The role of pituitary beta-endorphin in mediating corticotropin-releasing factor-induced antinociception

The hypothesis that blood-borne beta-endorphin modulates nociception was examined with corticotropin-releasing factor (CRF) as a potent and selective agent to stimulate its release from the pituitary gland. Intravenously administered CRF produced a dose-related antinociception in rats as determined by measuring paw-lick latencies on a 50 degrees C hot plate. A dose of 25 nmol/kg of CRF was comparable in both magnitude and duration of antinociception to a 7,500 nmol/kg (= 2.5 mg/kg) dose of morphine sulfate. The antinociceptive effect of CRF was blocked by both hypophysectomy and dexamethasone pretreatment, suggesting that it was mediated by hormone release from the anterior pituitary corticotrophs. Furthermore, the effect of CRF was antagonized by 1) naltrexone, 2) naltrexone methyl bromide, and 3) passive immunization with anti-beta-endorphin antiserum. Together, these data support the hypothesis that opiate-active, beta-endorphin, released by pituitary corticotrophs, participates in the physiological modulation of nociception in rats.

Local Anesthetics Potentiate Spinal Morphine Antinociception

Some investigators have postulated a synergistic analgesic effect of local anesthetic agents and opiates when given intrathecally or epidurally, but little objective evidence has been presented to quantitate such an effect. A study was therefore undertaken to compare in mice the antinociceptive effects of intrathecal injections of mixtures of morphine with bupivacaine or lidocaine with the effects of these agents when administered alone. The antinociceptive effects (tail-flick and hotp-late tests) of morphine (0.1-1.6 micrograms) with either bupivacaine, 25 micrograms, or lidocaine, 200 micrograms, were significantly greater than the effects of morphine or the local anesthetics when administered alone. When morphine was administered with the local anesthetics, the intensity and the duration of antinociception were greater, although the time courses of the effects resembled that of morphine administered alone. An enhanced effect was also observed when combinations of local anesthetics and low doses of morphine were used that by themselves had no or little effect. The addition of morphine did not affect the motor block produced by the local anesthetics. The results indicate a potentiating effect of local anesthetics on spinal morphine antinociception, a finding that may have important clinical implications.

GABA agonists enhance morphine and fentanyl antinociception in rabbit tooth pulp and mouse hot plate assays

AbstractParallel experiments in the rabbit tooth pulp and mouse hot plate paradigms were performed to elucidate the effect of pretreatment with the GABA mimetic compound muscimol (M) and diazepam (DZ) on the antinociceptive effect of both morphine sulfate (MS) and fentanyl citrate (F). The ED50 values for F in both rabbits and mice were lowered significantly (p ≤ 0.05) by pretreatment with either i.v. DZ or M in rabbits or i.p DZ or i.v. M in mice. There was a significant 7‐fold shift of the F dose‐response curve after pretreatment with M in rabbits and a 3‐fold shift in mice compared to controls; a 10‐fold shift after pretreatment with i.v. DZ in rabbits and a 2‐fold shift after i.p DZ in mice. The ED50 values for MS in both rabbits and mice were lowered significantly (p ≤ 0.05) by pretreatment with i.v. muscimol but not DZ (p ≤ 0.18). Similarly, pretreatment with i.v. M, in rabbits and mice, but not i.v DZ in rabbits or i.p DZ in mice, significantly shifted the dose‐response curves of MS to the left compared to controls. DZ and M i.v. significantly prolonged the duration of antinociception (rabbit) of an ED98 dose of MS and ED90 dose of F. Time to 50% maximal possible antinociceptive effect (MPE) increased from 240 min for MS + vehicle to 425 min for MS + DZ, and over 450 min for MS + M. Time to 50% MPE increased from 25 min for F + vehicle to 38 min for F + DZ. Similar results were observed for F + M. DZ pretereatment enhances the antinociceptive potency of 2X ED50 of F. In general, the average % MPE of F + DZ was twice tha tof F + vehicle over the first 20 min postopioid injection. A similar trend was noted following 2 × ED50 pf MS, whereas scopolamine had no significant effect. These results suggest that GABAA agonists, both direct M and indirect DZ enhance the antinociceptive effect of the opioids F and MS. since naloxone completely reversed this effect and scopolamine had no significant effect, this implies that GABAA agonists enhance opioid antinociception by an opioid and not a cholinergic mechanism.

The role of neurotransmitters in stress-induced antinociception (SIA)

The role of the neurotransmitters, norepinephrine, dopamine and serotonin in stress-induced antinociception (SIA) was examined by altering neurochemical tone with appropriate pharmacological tools. Quipazine (15.0 mg/kg, IP) a serotonin agonist, increased the peak and duration of antinociception following stress and BC-105 (3.0 mg/kg, IP), a serotonin antagonist, blocked the increase of tail-flick latency following stress. Clonidine (0.1 mg/kg, SC) an α 2 agonist, markedly decreased SIA whereas phenoxybenzamine (2.5 mg/kg, IP), an α 1 antagonist, increased the peak and duration of SIA. When dopaminergic tone was increased with apomorphine (0.05 mg/kg, SC) the increase of tail-flick latency after stress was markedly attenuated whereas blockage of dopamine receptors with haloperidol (2.5 mg/kg, IP) increased the peak and duration of SIA. Alterations of serotonergic, but not noradrenergic or dopaminergic, tone had similar effects on increased latency in tail-flick test produced by brain stimulation produced analgesia (SPA), morphine and SIA. These data support the hypothesis that alterations in tail-flick latency involves a serotonergic system.