ABSTRACT
Our previous studies have indicated that the thalamic nucleus submedius (Sm) is involved in modulation of nociception as part of an ascending component of an endogenous analgesic system consisting of spinal cord-Sm-ventrolateral orbital cortex (VLO)-periaqueductal gray (PAG)-spinal cord loop and that microinjection of 5-hydroxytryptamine (5-HT) into Sm produces antinociception. The aim of the present study was to examine whether the gamma-aminobutyric acid (GABA)ergic modulation is involved in the Sm 5-HT-evoked antinociception. Experiments were carried out on lightly anesthetized rats with an implanted cannula targeting the Sm nucleus. The microinjection of GABA(A) receptor antagonist bicuculline dose-dependently depressed the tail flick (TF) reflex. A smaller dose (100 ng) of bicuculline enhanced the inhibition of TF reflex produced by 5-HT application into Sm, whereas application of GABA (2.5 microg) did not influence the TF reflex but significantly attenuated the 5-HT-evoked inhibition. These results indicate that GABA(A) receptor may be involved in mediating the 5-HT-induced antinociception in Sm possibly through a disinhibition mechanism.
Subject(s)
Nociceptors/drug effects , Serotonin/pharmacology , Thalamic Nuclei/drug effects , gamma-Aminobutyric Acid/pharmacology , Analysis of Variance , Animals , Bicuculline/pharmacology , Brain Mapping , Dose-Response Relationship, Drug , Drug Interactions , GABA Antagonists/pharmacology , Male , Models, Neurological , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
Our previous studies have indicated that the thalamic nucleus submedius (Sm) is involved in modulation of nociception as part of an ascending component of an endogenous analgesic system consisting of spinal cord-Sm-ventrolateral orbital cortex (VLO)-periaqueductal gray (PAG)-spinal cord loop. Microinjection of 5-hydroxytryptamine (5-HT) into Sm produces antinociception and this effect is blocked by 5-HT(2) receptor antagonist. The aim of the present study was to examine whether the 5-HT(1) and 5-HT(3) receptors were also involved in the Sm 5-HT-evoked antinociception. Nociception was assessed in lightly anesthetized rats with radiant-heat-evoked tail flick (TF). 5-HT(1A) and 5-HT(3) receptor antagonists were microinjected into the Sm alone or in combination with a microinjection of 5-HT into the same Sm site. 5-HT(1A) receptor antagonist p-MPPI (0.87 nmol) facilitated the TF reflex; a lower dose (0.43 nmol) of p-MPPI significantly attenuated the Sm 5-HT-evoked inhibition of TF reflex. Microinjection of the 5-HT(3) receptor antagonist LY-278,584 (12 nmol) had no effect either on the TF reflex or on the Sm 5-HT-evoked inhibition. These results suggest that 5-HT(1A) receptor but not 5-HT(3) receptor is involved in mediating the 5-HT-evoked antinociception. Possible mechanisms of Sm 5-HT-induced descending antinociception are discussed.
Subject(s)
Pain Threshold/physiology , Posterior Thalamic Nuclei/physiology , Receptor, Serotonin, 5-HT1A/physiology , Receptors, Serotonin, 5-HT3/physiology , Analgesia , Animals , Microinjections , Nociceptors/drug effects , Nociceptors/physiology , Pain Threshold/drug effects , Posterior Thalamic Nuclei/drug effects , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1A/drug effects , Receptors, Serotonin, 5-HT3/drug effects , Reference Values , Reflex/drug effects , Reflex/physiology , Serotonin Antagonists/administration & dosageABSTRACT
Previous studies have shown that microinjection of morphine into the nucleus submedius (Sm) of the thalamus produces antinociception. The aim of the current study was to examine whether gamma-aminobutyric acid (GABA)ergic terminals in the Sm were involved in this antinociception. Under light anesthesia, the GABA(A) receptor antagonist bicuculline or agonist muscimol was microinjected into the Sm of the thalamus in Sm non-morphine-treated (control) or Sm morphine-treated (microinjection into the Sm in the thalamus) rats. Tail flick latencies (TFL) were measured in each of these groups of rats every 5 min. Bicuculline (100, 200, 500 ng in 0.5 microL) depressed the TF reflex in a dose-dependent fashion, and this effect was blocked by microinjection of the opioid receptor antagonist naloxone (0.5 microg) into the same Sm site. A small dose (100 ng) of bicuculline microinjected into Sm significantly enhanced the morphine-evoked inhibition of TF reflex. In contrast, administration of muscimol (250 ng) did not significantly influence the TF reflex in Sm non-morphine-treated rats, but it significantly attenuated the morphine-induced antinociception in the Sm morphine-treated rats. These results suggest that locally released GABA acting at GABA(A) receptors is involved in the modulation of Sm morphine-induced antinociception, and support the hypothesis that a disinhibitory effect elicited by morphine on GABAergic terminals in Sm may lead to activation of the Sm-ventrolateral orbital cortex (VLO)-perioqueductal gray (PAG) brainstem descending inhibitory system and depression of the nociceptive inputs at the spinal cord level.
