Serotonin contributes to the spinal antinociceptive effects of morphine.

This study was designed to determine if morphine administered intrathecally (IT) interacts with serotonergic or noradrenergic nerve terminals in the spinal cord to produce analgesia on the spinally mediated tail-flick test. Male Sprague-Dawley rats were fitted with IT catheters. One week later, animals were spinally pretreated with receptor antagonists selective for opioid, serotonin or alpha-adrenoceptors, and the ability of these agents to alter spinal morphine-induced antinociception was assessed. Morphine dose-dependently elevated tail-flick latency in a naltrexone-reversible manner. The serotonin receptor antagonists spiroxatrine (5-HT1A), pindolol (5-HT1B), ritanserin (5-HT2) and ICS 205-930 (5-HT3) attenuated the spinal analgesic effects of morphine. In contrast, the alpha 1 and alpha 2-adrenoceptor antagonists prazosin and yohimbine, respectively, did not alter morphine-induced elevations in tail-flick latency. These data substantiate earlier reports that spinal morphine-induced antinociception relies on an opioid receptor-mediated component in addition to a local serotonergic component. The finding that the alpha-adrenoceptor antagonists did not alter the antinociceptive effects of IT morphine suggests that spinal norepinephrine does not contribute to the analgesic effects of the opiate.

Analgesic effects of serotonin and receptor-selective serotonin agonists in the rat spinal cord.

1. Serotonin (5-HT) and selective 5-HT receptor agonists were administered intrathecally (i.t.) in rats, and the antinociceptive efficacy of these agents was assessed on the tail-flick and hot plate tests. 2. The 5-HT receptor agonists examined in this study included the 5-HT1A agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), the 5-HT1B agonist m-trifluoromethylphenylpiperazine (TFMPP), the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT3 agonist phenylbiguanide (PBG). 3. None of these agents produced significant elevations in tail-flick latency (TFL) at doses which produced elevations in hot plate latency (HPL). 4. In contrast, the i.t. dose of 5-HT which elevated TFL also produced analgesia on the hot plate test. 5. Serotonin-induced elevations in TFL were reversed by pindolol, ritanserin and ICS 205-930, suggesting that 5-HT interacts with more than one 5-HT site in the spinal cord to produce analgesia on the tail-flick test. 6. The finding that ritanserin reversed 5-HT-induced elevations in HPL suggests that the 5-HT2 site is primarily responsible for mediating the spinal antinociceptive effects of 5-HT on the hot plate test.

Acute and subchronic effects of methylenedioxymethamphetamine [(+/-)MDMA] on locomotion and serotonin syndrome behavior in the rat.

Specific behaviors comprising the serotonin syndrome (low body posture, forepaw treading, headweaving) and the autonomic signs of piloerection and salivation were determined and analyzed with locomotor activity in response to MDMA at three doses (2.5, 5.0, and 7.5 mg/kg). All behaviors were dose-responsive. Serotonin syndrome behaviors increased in both intensity and duration of response with increasing doses. In contrast, locomotion varied only in intensity. Subchronic injections, in the same group of animals, permitted an analysis of acute vs. subchronic effects on these same behaviors. Both the serotonin syndrome and locomotor behaviors were augmented on subsequent testing, indicating that, (+/-)MDMA, like amphetamine, is capable of producing behavioral sensitization.

The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat.

The effects of the recently classified Schedule I amphetamine analog, 3,4-methylenedioxymethamphetamine [+/-)-MDMA) on caudate and nucleus accumbens dopamine release and metabolism were studied by in vivo voltammetry and HPLC with electrochemical detection. Monitored over a 3 h period, the magnitude of increase in dopamine release and the onset of effect were dose-dependent and similar for both brain areas following the 2.5 and 5 mg/kg dose of the drug. However, responses were different for these brain regions using 10 mg/kg of MDMA; the magnitude of increase was greater and the onset of effect more immediate in caudate. Analysis of dopamine and DOPAC tissue content in both caudate and nucleus accumbens verified the voltammetry results. This study provides the first evidence that MDMA induces dopamine release in vivo and that this effect is region, time- and dose-dependent.