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UNLABELLED Inhaled anesthetics depress the response of spinal dorsal horn low-threshold (LT) neurons to peripheral receptive field stimulation. Part of that depression may be mediated by anesthetic interactions with gamma-aminobutyric acid type A (GABA(A)) and strychnine-sensitive glycine inhibitory neurotransmitter systems. In this electrophysiological study, we attempted to antagonize halothane depression of LT neurons by administering bicuculline (a competitive GABA(A) antagonist) and/or strychnine (a competitive glycine antagonist) systemically, alone or in combination, to decerebrate, spinal cord-transected rats. We observed that both bicuculline and strychnine, alone or in combination, significantly but only partially reversed halothane depression of LT neuronal responses to receptive field stimulation. The inability of bicuculline and strychnine, alone or in combination, to completely reverse halothane depression suggests that although GABA(A) and glycine systems are involved in the observed halothane depression, additional mechanisms of action are also required for halothane depression of LT spinal sensory neurons. IMPLICATIONS The results of this study support the hypothesis that halothane depression of spinal sensory neurons is mediated, but not completely, by the anesthetic effects on gamma-aminobutyric acid type A and strychnine-sensitive glycine neurotransmitter systems.

UNLABELLED We recently reported that gamma-aminobutyric acid type A- and strychnine-sensitive glycine receptor systems partially mediate halothane depression of spinal dorsal horn low-threshold neurons. Serotonin subtype 3 (5-HT(3)) receptors belong to the same ligand-activated ion-channel family as gamma-aminobutyric acid type A- and strychnine-sensitive glycine receptors, so we examined the possible involvement of 5-HT receptor systems in halothane depression of spinal sensory neurons. Extracellular recordings of spinal low-threshold neurons were obtained in decerebrate, spinally transected rats. Receptive field size and brush-induced activity were recorded in the presence or absence of 5-HT antagonists and in the presence or absence of 1.1% (1 minimum alveolar anesthetic concentration) halothane. In the absence of halothane, antagonists had no effect on receptive field size or brush-induced activity. In the presence of halothane, methysergide, a nonselective 5-HT antagonist, and tropisetron, a selective 5-HT(3) antagonist, significantly reversed the halothane-induced reduction in receptive field size but did not alter halothane depression of brush-induced activity. Methiothepin, a 5-HT(1) antagonist, and ketanserin, a 5-HT(2) antagonist, did not reverse halothane depression. These results support the hypothesis that 5-HT(3) receptors partially mediate some inhibitory effects of halothane on spinal dorsal horn neurons. IMPLICATIONS The results of this study support the hypothesis that halothane depression of spinal sensory neuronal responses to low-intensity stimuli is mediated, to a minor extent, by serotonin subtype 3 neurotransmitter systems.

The distribution of intrathecally administered 3H-morphine was examined by light microscopic autoradiography in rat spinal cord and temporal changes in silver grain localization were compared with results obtained from simultaneous measurements of analgesia. After tissue processing, radio-activity was found to have penetrated in superficial as well as in deeper layers (Rexed lamina V, VII, and X) of rat spinal cord within minutes after application. Silver grain density reached maximal values at 30 min in every region of cord studied. Radioactivity decreased rapidly between 30 min and 2 hr and then more slowly over the next 24 hr. In rats tested for responses to a thermal stimulus (tail flick test), intrathecal administration of morphine (5 and 15 micrograms) resulted in significant dose dependent analgesia that peaked at 30 min and lasted up to 5 hr (P less than 0.5). There was a close relationship between analgesia and spinal cord silver grain density during the first 4 hr of the study. It is postulated that the onset of spinal morphine analgesia depends on appearance of molecules at sites of action followed by the activation of anti-nociceptive mechanisms.

The purpose of this study was to examine the effects of alfentanil applied to the surface of the spinal cord and the effects of intravenously administered alfentanil on noxiously evoked activity of dorsal horn neurons. Extracellular single neuron recordings were obtained from wide dynamic range neurons in 26 decerebrate cats with transected spinal cords. Spinally administered alfentanil, 25 micrograms or 50 micrograms, caused 36 and 86% suppression of noxiously evoked activity, respectively. Maximum mean suppression was achieved at 24 and 21 min after 25 micrograms, and 50 micrograms, respectively. Intravenous naloxone, 0.1 mg, when tested, completely reversed the suppression. Spontaneous recovery to control values occurred within 2 hr. Intravenously administered alfentanil, 12.5 micrograms/kg or 25 micrograms/kg, produced suppression of 43 and 89%, respectively, with maximum mean suppression observed at the 6- and 3-min time points, respectively. Complete recovery after intravenous administration was seen within 30 min. This study, using a sensitive neurophysiologic assay, demonstrates the important differences in onset and duration of drug effects that must be considered when comparing the responses of spinal cord neurons to intravenously administered narcotics and narcotics applied directly to the surface of the spinal cord.

The development of a technique for studying spinal dorsal horn electrophysiology in intact, awake, drug-free cats enables the study of spinal sites and mechanisms of action of anesthetic and analgesic agents in a system that more closely reflects normal physiology. Using this technique, we reevaluated the effect of ketamine on spinal dorsal horn sensory transmission. The results of our study confirm previous work done in acute preparations. Ketamine (maximum dose 20 mg/kg) did not significantly reduce the response of low threshold (n = 11) dorsal horn neurons to low intensity sensory stimulation. However, that same dose of ketamine did suppress noxiously evoked activity of the two wide dynamic range neurons encountered in the study, while having a varied effect on neurons responsive to proprioceptive input (n = 7). These findings confirm that, in the intact animal with all modulatory systems intact, ketamine "dissociation" of low intensity tactile stimuli does not appear to involve a spinal mechanism of action. The results also support the importance of spinal sites of action for the analgesia produced by ketamine, as well as the importance of distinguishing between the anesthetic and analgesic effects of that drug.

The effects of sodium thiopental on the single-unit activity of cells in the nucleus reticularis gigantocellularis (NRGG) were examined in decerebrated cats. Only cells in the NRGC that responded exclusively to electrical stimulation of A-delta fibers (noxious stimulation) in the superficial radial nerve were studied. Sodium thiopental caused a significant, dose-dependent suppression of spontaneous and evoked neuronal activity of cells in the NRGC. Spontaneous activity was suppressed by 66% and 98% after intravenous administration of sodium thiopental, 2.5 mg/kg and 5.0 mg/kg, respectively. Evoked activity was suppressed by 65% and 79%. These findings, when added to previous reports of the suppressive effects of nitrous oxide, morphine sulfate, ketamine hydrochloride, and halothane, suggest the involvement of the NRGC in nociception and provide evidence that sodium thiopental significantly modifies the neuronal message about a noxious stimulus as recorded at the level of the NRGC.

The effects of intravenously administered fentanyl (25 micrograms/kg, n = 9; 50 micrograms/kg, n = 5) and alfentanil (12.5 micrograms/kg, n = 5; 25 micrograms/kg, n = 7) on the noxiously evoked, single-unit activity of cells in the nucleus reticularis gigantocellularis (NRGC) were studied in decerebrate cats. Only cells of the NRGC excited exclusively by supramaximal electrical stimulation of A delta fibers (noxious stimulation) of the superficial radial nerve were studied. The noxiously evoked activity of all cells in the NRGC was suppressed by the administration of opioids (by 58 and 88% for fentanyl, 25 micrograms/kg and 50 micrograms/kg, respectively; by 35 and 78% for alfentanil 12.5 micrograms/kg and 25 micrograms/kg, respectively). Fentanyl and alfentanil effects were antagonized by the intravenous administration of naloxone. These results indicate that opioid suppression of noxiously evoked activity is seen in neurons located in the brainstem, and thus suppression of brainstem neurons may be important in the production of fentanyl and alfentanil analgesia.

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 micrograms), yohimbine-reversible suppression of noxiously evoked activity in decerebrate, spinal cord-transected cats. In addition, combining ineffective intrathecal doses of morphine (25 micrograms) and clonidine (5 micrograms) 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 alpha 2-adrenergic receptors in clonidine analgesia.

The ability of 0.5% and 1.0% halothane to suppress neuronal activity of cells in the nucleus reticularis gigantocellularis (NRGC) was studied in decerebrate cats. These drug effects were examined in order to substantiate further the potential involvement of the NRGC in the modulation of transmission of pain information. Only cells of the NRGC, which were excited exclusively by electrical stimulation of A-delta fibers in the superficial radial nerve, were studied. Both concentrations of halothane caused a significant, dose-dependent reduction of spontaneous and evoked activity of all cells studied. These findings correlate well with previous reports of other anesthetics suppressing NRGC activity. In light of the selective depression by anesthetics and narcotic analgesics of spinal cord dorsal horn cells associated with noxious stimuli, these findings, when combined with anatomic, physiologic, and behavioral studies of NRGC, provide further evidence of the involvement of NRGC in the signaling of noxious stimuli and the analgesic effects of halothane exerted at this site.

The present study was designed to examine the effects of increased magnesium concentration on the nerve block produced by lidocaine, benzocaine, and QX 572 (a quaternary derivative of lidocaine). Desheathed whole sciatic nerves from northern Rana pipiens frogs were placed in a sucrose gap chamber and stimulated at various frequencies at supramaximal intensity for the activation of the compound action potential. After control studies, the nerve was bathed by a calcium-free frog Ringer's solution containing magnesium concentrations of 3.0, 10.0, or 20.0 mM with or without 0.5 mM lidocaine, 0.5 mM benzocaine, or 0.75 mM QX 572. Compound action potentials were measured, and nonfrequency and frequency dependent blocks were compared in each solution. Increased magnesium ion concentration, in the absence of local anesthetics, enhanced the nonfrequency dependent block but did not change the frequency dependent block. All three local anesthetics enhanced both types of block. Increased magnesium concentrations enhanced only the nonfrequency dependent benzocaine block. In contrast, increased magnesium enhanced both types of block produced by QX 572 and lidocaine. These results suggest a potentially important interaction between high magnesium concentrations and local anesthetic nerve blocks.