BACKGROUND: Spinal 5-hydroxytryptamine (5-HT) and adenosine have been shown to display an antinociceptive effect. The authors evaluated the characteristics of this drug interaction after the concurrent delivery of 5-HT and adenosine in combination at the spinal level. METHODS: Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. Nociception was induced by subcutaneous injection of formalin solution (5%, 50microliter) into the hindpaw. Fixed dose analysis and isobolographic analysis were used to determine the properties of the interaction. RESULTS: Intrathecal 5-HT dose-dependently suppressed the flinching response during phase 1 of the formalin test, whereas adenosine failed to affect the phase 1 flinching response. Both drugs attenuated the phase 2 flinching response in a dose-dependent manner. The intrathecal combination of 5-HT with a fixed dose of adenosine in phase 1 increased the antinociception of 5-HT alone, and isobolographic analysis in phase 2 revealed a synergistic interaction between intrathecal 5-HT and adenosine. CONCLUSIONS: Intrathecal 5-HT reduced the facilitated pain state and acute pain. In contrast, intrathecal adenosine alone did not affect acute pain significantly, but attenuated the facilitated pain state. Furthermore, 5-HT interacted synergistically with adenosine at the spinal level. Thus, this combination may offer a potential remedy for the treatment of tissue injury pain.
Acute Pain ; Adenosine* ; Animals ; Catheters ; Drug Interactions ; Formaldehyde* ; Humans ; Injections, Subcutaneous ; Male ; Models, Animal* ; Nociception ; Pain Measurement* ; Rats* ; Rats, Sprague-Dawley ; Serotonin* ; Spinal Cord

BACKGROUND: Spinal 5-hydroxytryptamine (5-HT) has been shown to display an antinociceptive effect, which is mediated by 5-HT receptors. Previous studies have revealed the presence of at least four types of 5-HT receptors in the spinal cord. The aim of this study was to assess the role of each spinal 5-HT receptor in the antinociception of intrathecal 5-HT using the formalin test. METHODS: Rats were implanted with lumbar intrathecal catheters. After the administration of 5-HT, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. To further clarify the role of the 5-HT receptors in the antinociception of 5-HT, several antagonists of 5-HT receptors were administered intrathecally 10 min before 5-HT delivery, and formalin was injected 10 min later. RESULTS: Intrathecal 5-HT dose-dependently suppressed flinching during phase 1 and 2 in the formalin test. 5-HT1B (GR 55562), 5-HT2C (N-desmethylclozapine), 5-HT3 (LY-278,584) and 5-HT4 (SDZ-205,557) receptors antagonists reversed this antinociception by 5-HT during both phases in the formalin test. 5-HT1A receptor antagonist (WAY-100635) decreased antinociception by 5-HT in phase 2, but not in phase 1. A 5-HT1D receptor antagonist (BRL 15572) did not antagonize the antinociception of 5-HT in either phases. CONCLUSIONS: Spinal 5-HT1B, 5-HT2C, 5-HT3 and 5-HT4 receptors, but not the 5-HT1D receptor, are involved in the antinociception of serotonin in the facilitated state and in the acute pain evoked by a formalin stimulus. The 5-HT1A receptor seems to play a role in 5-HT-induced antinociception in the facilitated state.
Acute Pain ; Animals ; Catheters ; Formaldehyde ; Pain Measurement ; Rats* ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT1D ; Receptors, Serotonin ; Receptors, Serotonin, 5-HT4 ; Serotonin* ; Spinal Cord*

BACKGROUND: Cyclic guanosine monophosphate (cGMP) plays an important role in the modulation of nociception. Although local sildenafil produces antinociception, by increasing cGMP through the inhibition of phosphodiesterase 5, the effect of spinal sildenafil has not been determined. The authors evaluated the effects of intrathecal sildenafil on the nociceptive behavior evoked by formalin injection and thermal stimulation. METHODS: Lumbar intrathecal catheters were implanted into rats, with formalin and Hot-Box tests used as nociceptive models. The formalin-induced nociceptive behavior (flinching response) and withdrawal latency to radiant heat were measured, and the general behaviors also observed. RESULTS: The intrathecal administration of sildenafil produced dose-dependent suppression of the flinches in both phases in the formalin test, and increased the withdrawal latency in the Hot-Box test. No abnormal behaviors were noted. CONCLUSIONS: Sildenafil, an inhibitor of phosphodiesterase 5, is active against the nociceptive state evoked in the spinal cord by formalin and thermal stimulations. Accordingly, spinal sildenafil may be useful in the management of pain.
Animals ; Catheters ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Formaldehyde ; Guanosine Monophosphate ; Hot Temperature ; Nociception* ; Pain Measurement ; Rats* ; Spinal Cord ; Sildenafil Citrate

BACKGROUND: Cannabinoids have shown antinociceptive action. The aims of this study were to examine the effect of chronic infusion of a cannabinoids receptors agonist (WIN 55, 212-2) for thermal nociception at the spinal level, and to also observe the development of toxicity. METHODS: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters with the nociceptive response (withdrawal response latency) determined by exposing the plantar surface of the hindpaw to radiant heat. Initially, the effect of intrathecal WIN 55, 212-2 was evaluated followed by the change in the effect at 1, 2, 3 and 4 weeks after repeated infusion. Finally, the histopathological findings were assessed 1 and 4 weeks following the infusion of WIN 55, 212-2. RESULTS: Intrathecal WIN 55, 212-2 was found to produce a limited antinociception during the thermal test. %MPE of WIN 55, 212-2 at 1, 2, 3, and 4 weeks after infusion was not different from each other. No abnormal pathological findings were observed following a chronic intrathecal infusion of WIN 55, 212-2. CONCLUSIONS: WIN 55, 212-2, a cannabinoids receptors agonist, may be useful in the management of thermal nociception, without changing the effectiveness or causing the toxicity following a chronic infusion at the spinal level.
Animals ; Cannabinoids* ; Catheters ; Hot Temperature ; Humans ; Male ; Nociception ; Rats* ; Rats, Sprague-Dawley

BACKGROUND: Serotonin 3 receptor is involved in the modulation of nociceptive transmission in the spinal cord. The serotonin 3 receptor antagonist has been used for the management of opioid-induced nausea and vomiting. The aim of this study was to examine whether the analgesic effect of morphine is antagonized by serotonin 3 receptor antagonists at the spinal level. METHODS: Rats were implanted with lumbar intrathecal catheters. For nociception, a formalin solution (5%, 50microliter) was injected into the hind paw of male Sprague-Dawley rats. To determine whether the effect of intrathecal morphine was mediated via serotonin 3 receptors, serotonin 3 receptor antagonists were intrathecally administered 10 min prior to the morphine delivery. Following the formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. RESULTS: Intrathecal morphine produced a dose-dependent suppression of the flinches in both phases during the formalin test. The analgesic action of morphine was not reversed by serotonin 3 receptor antagonists (LY-278, 584, ondansetron), which had little per se effect on the formalin-induced nociception. CONCLUSIONS: Spinal serotonin 3 receptors may not be involved in the analgesia of morphine on a nociceptive state evoked by a formalin stimulus.
Analgesia ; Animals ; Catheters ; Formaldehyde ; Humans ; Male ; Morphine* ; Nausea ; Nociception ; Pain Measurement ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT3 ; Serotonin* ; Spinal Cord ; Vomiting