J. G. Collins

Synergistic antinociceptive interaction after epidural coadministration of morphine and lidocaine in rats.

BackgroundClinically, epidural coadministration of opioids and local anesthetics has provided excellent analgesia for various types of pain. However, information about the interaction of these drugs when administered epidurally is limited. Therefore, we evaluated the antinociceptive interaction between morphine and lidocaine on both somatic and visceral noxious stimuli in the rat. MethodsMale Sprague-Dawley rats weighing 300–350 g had epidural catheters implanted at T13–L1. Every rat was tested with both the tail flick test, a somatic noxious stimulus, and the colorectal distension test, a visceral noxious stimulus. In the colorectal distension test, the response threshold was defined by the pressure within the intracoionic balloon required to trigger abdominal contraction. Tail flick latency and colorectal distension threshold were measured before and for 180 min after the administration of morphine, lidocaine, or combinations of those drugs. To characterize the interaction, isobolographic analysis was performed with a fixed morphine: lidocaine dose ratio of 1:1,000. ResultsEpidural morphine (0.1–10 μg) and lidocaine (100–800 μg) increased the tail flick latency and colorectal distension threshold in a dose- and time-dependent fashion. The epidural injection of morphine (0.1–1 μg) mixed with lidocaine (100 or 200 μg) significantly increased the peak effect and prolonged the duration of effects compared with each drug alone in both nociceptive tests. Areas under the curves, calculated to express overall magnitude and duration of antinociceptive effects, were significantly increased by combinations as compared with each drug alone, especially with morphine 0.1 μg and lidocaine 100 or 200 μg, each of which alone produced no change in the area under the curve. Isobolographic analysis revealed that epidural morphine and lidocaine interact synergistically at 10, 20, and 30 min after injection in both somatic and visceral nociception tests. Both potency ratio analysis and fractional analysis confirmed the finding of the isobolographic analysis. Epidural naloxone antagonized the antinociceptive effects produced by the combination. ConclusionsThese data demonstrate that epidurally coadministered morphine and lidocaine produce synergistic analgesia and prolong the duration of analgesia in tests of somatic and of visceral nociception.

Interaction between opiate subtype and alpha-2 adrenergic agonists in suppression of noxiously evoked activity of WDR neurons in the spinal dorsal horn

Several studies have demonstrated synergistic antinociception following low-dose administration of morphine and alpha-2 adrenergic agonists at the spinal level. This study was carried out in order to identify the opiate subtypes that are likely to be involved in such synergistic suppression of noxiously evoked activity of wide-dynamic-range (WDR) neurons in the dorsal horn of the spinal cord. We also examined the effect of opiate antagonists and alpha-2 adrenergic antagonists on the suppression produced by opiate or alpha-2 adrenergic agonists. Extracellular activity of single WDR neurons in the spinal dorsal horn, which was evoked by a radiant heat stimulus (51 degrees C), was recorded in decerebrate, spinally transected cats. Agonists were administered spinally and antagonists intravenously. In the synergism study, ineffective doses of the moderately selective mu agonist morphine (25 micrograms), the delta agonist DADL (20 micrograms), and the selective delta agonist DPDPE (30 micrograms), when combined with an ineffective dose of the alpha-2 adrenergic agonist clonidine (5 micrograms) produced significant synergistic suppression of noxiously evoked WDR neuronal activity. However, the ineffective or slightly effective dose of the selective mu agonist DAGO (1 or 1.5 micrograms, respectively) did not show any synergistic action with clonidine. Furthermore, the synergism between morphine and clonidine was reversed by the selective delta antagonist ICI 174,864. We interpret these results to indicate that opiates interact at spinal delta receptors to produce a synergistic suppression of evoked WDR neuronal activity in the presence of spinal clonidine. An alternative explanation is that ICI 174,864 may interact in some way with alpha-adrenergic systems.(ABSTRACT TRUNCATED AT 250 WORDS)

WDR response profiles of spinal dorsal horn neurons may be unmasked by barbiturate anesthesia

&NA; The number of WDR (convergent, multireceptive) neurons encountered in the spinal dorsal horn of physiologically intact, awake, drug‐free cats has been much smaller than expected (9% in intact, drug‐free animals). Control studies in barbiturate‐anesthetized or spinal cord transected animals indicate that the dearth of WDR neurons was not just an artifact of the chronic recording technique. In those preparations WDR neurons represented 34% and 61% of the sample, respectively. Initial studies in which the effects of light barbiturate anesthesia on spinal dorsal horn neurons (n = 12) have been examined revealed that a 20 mg/kg dose of pentobarbital can, in some neurons (n = 4), unmask thermally evoked activity that was not present in the intact, drug‐free animal. Responses to noxious mechanical stimuli were also enhanced following barbiturate administration. These changes resulted in a reclassification of neural type from low threshold in the intact, awake, drug‐free animal to WDR in the anesthetized animal.

Intrathecal clonidine suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats.

The analgesic effectiveness of perispinal clonidine administration prompted us to evaluate clonidine effects on spinal dorsal horn wide dynamic range neurons. Intrathecal clonidine produced a dose-dependent (10 and 30 μg), yohimbine-reversible suppression of noxiously evoked activity in decerebrate, spinal cord-transected cats. In addition, combining ineffective intrathecal doses of morphine (25 μg) and clonidine (5 μg) produced statistically significant, reversible suppression of noxiously evoked activity. The time course of suppression was similar to that observed behaviorally. These results support the role of spinal α2-adrenergic receptors in clonidine analgesia.

Effects of Halothane on Spinal Neuronal Responses to Graded Noxious Heat Stimulation in the Cat

This study was undertaken to examine the dose–response effects of clinical concentrations of halothane on activity of widedynamic-range (WDR) neurons in the dorsal horn of the spinal cord of the decerebrate, spinal cord-transected cat. All cells (n = 40) responded maximally to high-intensity (greater than 45 C) noxious heat stimulation. Following administration of halothane, 0.5, 1.0, and 1.5 per cent, the mean spontaneous discharge frequency was significantly decreased (P < 0.01) by 44, 74, and 87 per cent, respectively. The mean evoked discharge frequencies were also significantly decreased at all temperatures (46, 48.5, 51 C) by all concentrations of halothane. The slope of the regression line relating heat intensity and evoked neuronal discharge frequency was significantly decreased (P < 0.01) with both 1.0 and 1.5 per cent halothane by 46 and 75 per cent, respectively. Since the spinal cord was transected, these results indicate that these effects were the result of a direct action at the level of the spinal cord. The neuronal activity that was suppressed was evoked by stimuli that were exclusively noxious. This substantiates the ability of halothane to modify the transmission of noxious information at the spinal cord level, and thus explains a mechanism by which halothane may induce analgesia.

Visceral Antinociceptive Effects of Spinal Clonidine Combined with Morphine, [D-Pen sup 2, D-Pen sup 5] Enkephalin, or U50,488H

BACKGROUND Visceral pain is an important component of many clinical pain states. The perispinal administration of drug combinations rather than a single agent may reduce side effects while maximizing analgesic effectiveness. The purpose of this study was to examine the nature of interactions between an alpha 2-adrenergic agonist (clonidine) and a mu-opioid agonist (morphine), a delta-opioid agonist ([D-Pen2, D-Pen5] enkephalin [DPDPE]), or a kappa-opioid agonist (U50,488H). METHODS Colorectal distension was used to elicit a nociceptive visceromotor response (contraction of abdominal musculature) in rats. The ability of intrathecally administered clonidine alone or in combination with morphine, DPDPE, or U50,488H to alter thresholds for the production of the visceromotor response was examined. RESULTS Clonidine produced dose-dependent reduction in threshold. U50,488H, at the doses tested, showed no synergistic interaction with clonidine. CONCLUSIONS Spinal combinations of alpha 2-adrenergic and mu- or delta- but not kappa-opioid agonists may be beneficial in the control of visceral pain.

SEROTONERGIC MEDIATION OF SPINAL ANALGESIA AND ITS INTERACTION WITH NORADRENERGIC SYSTEMS

Serotonin was administered intrathecally onto cat spinal cords to evaluate the pharmacology by which it suppresses noxiously evoked activity of wide-dynamic-range (WDR) neurons in the spinal dorsal horn. Doses of 500, 1,000 and 2,000 micrograms serotonin produced significant suppression of the mean noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord (21, 44, and 69% at 30 min, respectively). The dose-dependent effects were partially reversed by the intravenous administration of the serotonin antagonist methysergide (1 or 2 mg). Intravenous administration of the alpha 2-adrenergic antagonist yohimbine (0.5 or 1.0 mg/kg) produced a significant antagonism of the effects of serotonin. In contrast to the effects of methysergide and yohimbine, intravenous administration of naloxone or the alpha 1-antagonist corynanthine had no effect upon the suppressive effects of serotonin. The combination of low-dose serotonin and low-dose clonidine produced a supraadditive effect (30% at 30 min). These data support the concept that noradrenergic systems, possibly through an alpha 2-adrenergic mechanism, are involved in the modulation of spinal WDR neurons by serotonin.

Contrasting Actions of Intrathecal U50, 488H, Morphine, or [D-Pen sup 2, D-Pen sup 5] Enkephalin or Intravenous U50, 488H on the Visceromotor Response to Colorectal Distension in the Rat

Background Visceral sensations are an important component of many clinical pain states. It is apparent that intrathecal pain relief may be more effective if appropriate combinations of drugs rather than a single agent can be used. The purpose of this study was to examine the relative contribution of opioid receptor subtypes to visceral antinociception using colorectal distension as a visceral pain model.

Direct opioid application to peripheral nerves does not alter compound action potentials.

The identification of opiate receptors on primary afferent fibers near the dorsal root ganglia suggests that opiates may be able to affect conduction in primary afferent nerve fibers. We examined the effect of directly applied, preservative-free morphine sulfate (0.1 mg/kg) and fentanyl citrate (25 μg/kg) on the A beta, A delta, and C components of the compound action potential of the superficial radial nerve in decerebrate cats (n = 18). Neither drug caused any significant change in the area under the curve of any of the compound action potentials studied. These data indicate that systemically administered opiates are unlikely to cause changes in primary afferent nerve conduction.

The effects of an intrathecal NMDA antagonist (AP5) on the behavioral changes induced by colorectal inflammation with turpentine in rats.

Visceral pain, especially that associated with inflammation of visceral organs, is poorly understood and difficult to treat clinically. The purpose of this study was to investigate the effects of intrathecal 2-amino-5-phosphonovaleric acid (AP5, a competitive NMDA antagonist) upon a visceromotor response to distension of colonic tissue inflamed by exposure to turpentine. All experiments were conducted under pentobarbital anesthesia. Animals were prepared with a laminectomy from T12 to L1 to facilitate intrathecal drug administration. Colonic distension thresholds for a visceromotor response were determined in the presence and absence of AP5. Animals were divided into two groups. The NS group received 50 microl of saline intrathecally and the AP5 group 10 mM of AP5 in 50 microl saline. After baseline measurements, intrathecal drugs were administered. Five minutes later, the effects of intrathecal drugs were measured, then 1 ml of 25% turpentine was administered anorectally. Subsequent measurements were made every 5 minutes for the next 90 minutes. Visceromotor thresholds to colorectal distension (CRD) were significantly decreased 50 min after turpentine administration in the NS group. There was no threshold change in the AP5 group. This study suggests that the administration of the competitive NMDA receptor antagonist AP5 in this model blocks the effect of turpentine sensitization on visceromotor response to CRD. The absence of AP5 effects in animals not sensitized by turpentine suggests that NMDA systems may be involved in the sensitization.