Luke M. Kitahata

Lamina-specific suppression of dorsal-horn unit activity by morphine sulfate.

The effects of morphine sulfate on single-unit activities of various dorsal-horn Rexed laminae were studied using an extracellular microelectrode recording technique in decerebrate spinal cats. Morphine sulfate, 0.5, 1, and 2 mg/kg, iv, suppressed in a dose-related manner spontaneous single-unit activities in Rexed laminae I and V, known to respond principally to noxious stimuli, but did not affect spontaneous activities in laminae IV and VI, known to respond to non-noxious stimuli. Morphine sulfate, I mg/kg, iv, also suppressed unit activities of laminae I and V evoked by noxious cutaneous stimuli by 35.5 ± 7.1 and 48.2 ± 4.0 (&OV0335; ± 1 SE) per cent, respectively. The selective action of morphine on dorsal horn nociceptors may partially explain the analgesic action of morphine at the spinal level.

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)

Lamina-specific Suppression of Dorsal-horn Unit Activity by Ketamine Hydrochloride

The effects of ketamine hydrochloride on single-unit activities of various dorsal-horn Rexed laminae were studied with an extracellular microelectrode recording technique in decerebrate spinal cats. Ketamine hydrochloride, 2.5 mg/kg, iv, suppressed spontaneous single-unit activities of laminae 1 and 5 by 23 and by 43 per cent, respectively, while spontaneous activity of lamina 4 and that of lamina 6 were not significantly affected. This dose suppressed evoked unit activities of laminae 1 and 5 by 44 and by 64 per cent, respectively. As laminae 1 and 5 are known to respond principally to noxious stimali, a partial explanation for the analgesic effect of ketamine may be lamina-specific suppression of neuronal activity.

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.

Direct visualization of the lumbosacral epidural space through the sacral hiatus.

M yeloscopy, or the direct visualization of the spinal canal and its contents, was first reported in 1931 from the pioneering work of Michael Burman (1). With each decade since then, myeloscopists and epiduroscopists have attempted to develop a means of visualization that would be easy and safe to apply to medical practice. Unfortunately, until the recent advent of both flexible fiberoptic light sources and optics (2) this could not be achieved. The recent work of Heavner et al. (3) and Schutze and Kurtze (4) indicated that the lumbar epidural space can be accessed with fiberoptic systems. However, the angle of entry into the lumbar epidural and the intrathecal spaces made steering difficult. Steering is thought to be a required feature to make this technology clinically useful. Described in this report is passage of a fiberoptic system from the sacral hiatus into a saline-expanded lumbar epidural space. Most importantly, the straight entry allowed for easier maneuvering of the fiberoptic scope and laid the foundation for future fiberoptic guided procedures.

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.

An Analgesic Action of Intravenously Administered Lidocaine on Dorsal-horn Neurons Responding to Noxious Thermal Stimulation

Using extracellular single-unit recording techniques, effects of intravenously administered lidocaine on dorsal-horn nociceptive neurons were studied in cats made decerebrate whose spinal cords had been transected. Thirty-seven neurons in Rexed lamina V responding to high-threshold mechanical and noxious thermal stimuli (radiant heat, using Hardy-Wolff-Goodell dolorimeter) were studied. Lidocaine hydrochloride, 2.5, 5, and 10 mg/kg, iv, produced dose-related suppression of both spontaneous activity and responses of these neurons to noxious thermal stimulation. Spontaneous discharge frequencies at maximum suppression, observed 3--7 min after administration of each of the three doses of lidocaine were 64 +/- 14 (mean +/- 1 SE), 32 +/- 8, and 25 +/- 9 per cent of control values, respectively; responses to noxious thermal stimuli were 83 +/- 5, 52 +/- 8, and 39 +/- 7 per cent of the control values, respectively. Threshold skin temperature to noxious thermal stimulation increased from 44.7 +/- 0.4 C (control) to 46.3 +/- 0.7 C with lidocaine, 5 mg/kg (P less than 0.05), to 47.8 +/- 0.8 C with lidocaine, 10 mg/kg (P less than 0.01). The times necessary for recovery varied in a dose-related fashion. Plasma lidocaine concentrations 5 min after lidocaine, 5 mg/kg, averaged 3.6 +/- 0.7 microgram/ml. These data support the clinical impression that intravenously administered lidocaine produces analgesia at plasma concentrations of 3--10 microgram/ml. It is suggested that lidocaine may block conduction of nociceptive impulses, at least in part, by suppression of spinal-cord nociceptive neurons.

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.