| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
Anesth Analg 2003;96:1072-1078 © 2003 International Anesthesia Research Society
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
-Methyl-5-Hydroxytryptamine, a 5-Hydroxytryptamine2A/2C Receptor Agonist, in Two Rat Models of Sustained Pain
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Type 2 serotonin (5-hydroxytryptamine [5-HT]2) receptors in the spinal cord have been reported to mediate antinociception using pain threshold tests, but little is known about the actions of spinal 5-HT2 receptors in sustained pain. In rats, we examined antinociceptive effects of the intrathecal administration of a 5-HT2A/2C receptor agonist,
-methyl-5-HT maleate (-m-5-HT), using the formalin test and the chronic constriction injury (CCI) model. An intrathecal catheter was implanted for injection of drugs. In the formalin test, flinches were counted from Minute 1 to 2 and Minute 5 to 6 (Phase 1) and then for 1-min periods at 5-min intervals from 10 to 60 min (Phase 2). In rats with CCI, hind paw withdrawal latency after thermal stimulation was measured. In the formalin test, intrathecal administration of -m-5-HT (1 to 100 µg) dose-dependently suppressed the number of flinches in both Phases 1 and 2. In the CCI model, intrathecally administered -m-5-HT (10 to 100 µg) attenuated thermal hyperalgesia in a dose-dependent manner. These effects were reversed by intrathecal pretreatment with a 5-HT2A/2C antagonist, ketanserin (30 µg), or a muscarinic receptor antagonist, atropine (30 µg). These findings suggest that spinal 5-HT2A/2C receptors mediate antinociception in inflammatory pain and neuropathic pain, and the muscarinic receptors contribute to this action. IMPLICATIONS: Activation of spinal 5-hydroxytryptamine2A/2C receptors mediate antinociception in rat-sustained pain models such as inflammatory pain and neuropathic pain, and spinal muscarinic receptors are involved in this action.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The descending serotonergic bulbospinal pathway participates importantly in endogenous antinociceptive mechanisms. Activation of the pathway increases turnover and release of serotonin (5-hydroxytryptamine [5-HT]). Intrathecally administered 5-HT produces antinociception in rats, rabbits, and cats (1). In rats, this has been demonstrated using such measures as the tail-flick test (2), paw-pressure test, and formalin test (3). These reports indicate that activation of 5-HT receptors in the spinal cord mediate antinociception. Several 5-HT receptor subtypes have been defined and pharmacologically demonstrated in the central nervous system, and there are at least three families of 5-HT receptors in the spinal cord, namely 5-HT1, 5-HT2, and 5-HT3 receptors (4). Although there is controversy regarding roles of individual 5-HT receptor subtypes, these three receptors may be involved in nociceptive transmission in the spinal cord (5).
Among 5-HT2 receptors, both 5-HT2A and 5-HT2C receptors’ messenger RNA are present in the dorsal horn of the rat spinal cord shown in a study with in situ hybridization (6). Whereas several studies demonstrated involvement of spinal 5-HT2A/2C receptors in antinociception using the tail-flick test (7), hot-plate test (8), and colorectal distension test (9), little is known about the antinociceptive effect of spinal 5-HT2A/2C receptors in models of sustained pain such as inflammatory or neuropathic pain. Recently, we demonstrated that intrathecal administration of 5-HT2A/2C receptor agonists, but neither 5-HT1 nor 5-HT3 agonists, produced antiallodynic action in a rat model of neuropathic pain produced by L5 and L6 spinal nerve ligation (10). The results suggested that spinal 5-HT2A/2C receptors are involved in antinociception in sustained pain.
Formalin injection into the rat paw produces biphasic pain-related behaviors, whereas chronic constriction injury (CCI) of the rat sciatic nerve by loose ligation leads to thermal hyperalgesia. These models are considered to mimic certain types of inflammatory or neuropathic pain. Therefore, we investigated antinociceptive effects of an intrathecally administered 5-HT2A/2C receptor agonist using the formalin test and CCI model.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This investigation was conducted in accordance with a protocol approved by the Animal Care Committee of Gunma University. Experiments were conducted in male Wistar rats weighing 280 to 320 g.
The surgical procedure described by Bennet and Xie (11) was used to produce CCI. Anesthesia was administered by inhalation of 2% to 3% isoflurane. After a local incision, the right and left biceps femoralis were bluntly dissected at mid-thigh to expose the sciatic nerves. Four 4-0 chromic gut sutures were tied loosely with a square knot around the right sciatic nerve, whereas the left sciatic nerve was not manipulated after mobilization. The spaces between the four ligatures were approximately 1 mm. Incisions were closed with 3-0 silk sutures, and rats were allowed to recover from anesthesia. After undergoing this sciatic nerve constriction procedure, rats were maintained individually with free access to food and water in cages with solid floors covered by 3–6 cm of sawdust.
An intrathecal catheter was inserted before drug testing using a modification of the method described by Yaksh and Rudy (12). Rats were anesthetized with 2% to 3% isoflurane in oxygen, and a polyethylene catheter (PE 10) was advanced for 8.5 cm in a caudal direction through an incision in the atlanto-occipital membrane until the upper portion of the lumbar enlargement was reached. After catheter implantation, rats were housed individually with free access to food and water and allowed to recover for 7 days. Rats showing neurologic deficits after surgery were killed promptly with a barbiturate overdose.
For the formalin test, formalin (50 µL of a 5% solution) was subcutaneously injected into the plantar surface of the right hind paw with a 30-gauge needle. The rat was placed in an open Plexiglas enclosure to allow unobstructed observation of the formalin-injected paw. Flinching was readily identified and was characterized as rapid, brief flexion withdrawal of the injected paw. Pain-related behavior was quantified by periodically counting those spontaneous flinching movements (13). Flinches were counted for 1-min periods from Minute 1 to 2 and from Minute 5 to 6 (Phase 1) and also at 5-min intervals during the period from 10 to 60 min after formalin injection (Phase 2). After these observations, rats were killed promptly with a barbiturate overdose.
In rats with CCI, paw withdrawal latency (PWL) after thermal stimulation was measured using the Hargreves et al. (14) method. Rats were placed in a clear plastic cage (10 x 20 x 24 cm) with an elevated floor of clear glass (thickness, 2 mm). A radiant heat source (eye projector halogen lamp JRC-12V-100W; Iwasaki Electric, Tokyo, Japan) with an aperture diameter of 5 mm was placed in a movable holder beneath the raised glass floor. The thermal test system was calibrated so that the average response latency in 10 normal rats was maintained at 10 s before initiation of an experimental series. To initiate testing, a rat was placed in the box and allowed to habituate for 5 to 10 min. The radiant heat source then was positioned beneath the plantar surface of one hind paw in contact with the glass floor. The light was activated, initiating a timing circuit. The interval between application of the light beam and a brisk hind paw withdrawal response was measured. This value was assigned as the PWL. The radiant heat source was removed when no response occurred within 20 s (cutoff time). Before intrathecal drug injection, the hind paws were tested alternately 3 times to obtain baseline data, with 5-min intervals between consecutive tests. Both paws were tested alternately at 5 min, 15 min, 30 min, 45 min, and 60 min after the injection.
General behavior of the rats was carefully monitored. Motor function was evaluated with the placing reflex and the righting reflex. Sedation was assessed in terms of spontaneous movement such as grooming, chewing, and ambulation, as well as evoked movement (a startle reflex evoked by tapping on the cage).
We used -methyl-5-HT maleate (-m-5-HT; 1 to 100 µg) as a 5-HT2A/2C receptor agonist. For the antagonist studies, ketanserin (30 µg) was used as a 5-HT2A/2C receptor antagonist. As interactions with other neurotransmitters such as acetylcholine (ACh) (15) or 
-aminobutyric acid (GABA) (16) have been implicated in activation of 5-HT2A/2C receptors, a muscarinic receptor antagonist (atropine; 30 µg), a GABAA receptor antagonist (bicuculline; 0.03 µg for the formalin test and 0.3 µg for the CCI model), and a GABAB receptor antagonist (phaclofen; 30 µg) were used as antagonists. Doses of antagonists were selected according to previous reports (10,15,17) . All drugs were purchased from Research Biochemicals (Natick, MA). Drugs were dissolved in physiologic saline in concentrations that allowed intrathecal injections in 10-µL volumes. Control rats were given 10 µL of physiologic saline intrathecally. Drugs and saline were followed by 10 µL of saline to flush the catheter. In the formalin test, -m-5-HT was intrathecally administered 5 min before the formalin injection. For antagonist studies, the antagonist was administered first, followed by -m-5-HT 5 min later.
For the formalin test, data from Phase 1 and Phase 2 were independently considered. In each phase, the cumulative number of flinches during the observed intervals was calculated for each rat. To evaluate dose-dependency, statistical comparisons were made by analysis of variance (ANOVA), followed by the Tukey test for multiple comparisons. For antagonist studies, the number of flinches induced by 100 µg of -m-5-HT and the number observed in the presence of the antagonist were compared by ANOVA. In the thermal nociceptive test using rats with CCI, the PWL were converted to maximal possible effect (%MPE) according to the formula: %MPE = ([postdrug latency - predrug latency]/[cutoff time - predrug latency]) x 100. Then, estimated areas under the time-course curves (AUC) were calculated using the trapezoidal rule over the entire time course. To evaluate dose-dependency, data for %MPE and AUC were compared using ANOVA, followed by the Tukey test for multiple comparisons. ANOVA was used to compare the PWL of the injured paw with that of the noninjured paw at each dose. For antagonist studies, AUC in rats treated with 100 µg of -m-5-HT and those observed in the presence of the antagonist were compared by ANOVA. Statistical significance was defined as P < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Intrathecal administration of all doses of
-m-5-HT tested showed no motor dysfunction or sedative effect. In rats treated with saline, subcutaneous formalin injection into the plantar surface of the right hind paw produced biphasic flinching behavior (Fig. 1A). Intrathecal administration of 100 µg of -m-5-HT caused a significant reduction in the number of flinches of the injected paw in both Phase 1 and Phase 2. These effects were dose-dependent for doses between 1 and 100 µg (Fig. 1B; Phase 1, P < 0.01 by ANOVA; Fig. 1C; Phase 2, P < 0.01 by ANOVA). Intrathecal pretreatment with ketanserin or atropine attenuated the antinociceptive effects produced by 100 µg of -m-5-HT in Phase 1 (Fig. 2B; flinches without antagonist, 6.8 ± 2.0; with ketanserin, 22.7 ± 2.6; with atropine, 24.3 ± 4.9) and Phase 2 (Fig. 2C; flinches without antagonist, 21.2 ± 8.6; with ketanserin, 58.2 ± 11.9; with atropine, 57.0 ± 9.1). Pretreatment with bicuculline or phaclofen abolished the effects of -m-5-HT in Phase 1 (Fig. 2B; flinches with bicuculline, 22.0 ± 2.7; with phaclofen, 16.2 ± 1.7), but no abolition occurred in Phase 2 flinches (Fig. 2C).
|
P < 0.05 compared with rats receiving 10 µg of
|
In all rats undergoing the thermal test, hyperalgesia of the paw affected by nerve injury was evident. The PWL on the noninjured (left) side was 9.7 ± 0.2 s, whereas the PWL on the injured (right) side was 6.0 ± 0.2 s (P < 0.01 by ANOVA). The time course of the antihyperalgesic effect after intrathecal administration of
-m-5 HT is illustrated in Figure 3A. The maximum dose of -m-5-HT (100 µg) produced an antihyperalgesic effect at 5, 15, and 30 min after the injection, whereas an antihyperalgesic effect was seen only at 5 min after the injection of 60 µg. At 10 and 30 µg, no effect was found at any time point. Peak effects always appeared at least 5 min after the injection. The AUC increased dose-dependently from 10 to 100 µg (Fig. 3B; P < 0.01 by ANOVA). Intrathecal pretreatment with ketanserin or atropine reversed the antihyperalgesic effects produced by 100 µg of -m-5-HT (Fig. 4B; AUC without antagonist, 1266 ± 204; with ketanserin, 150 ± 199; with atropine, 122 ± 133, respectively). Intrathecal pretreatment with bicuculline or phaclofen showed no reversal effect (Fig. 4). Figure 5 shows peak %MPE (5 min after injection) of each paw at each dose of -m-5-HT and in the saline-treated group. Dose-dependent increases of the PWL were found on the hyperalgesic (injured) side (P = 0.01 by ANOVA) but not on the normal (noninjured) side (P = 0.31 by ANOVA). Intrathecal administration of antagonists alone at the same doses used for pretreatment did not alter the number of flinches or the PWL compared with a saline-treated group (data not shown).
|
|
|
P < 0.05 compared with the noninjured paw at the same dose. |
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Intrathecal injection of
-m-5-HT produced a dose-dependent antinociceptive effect in both the formalin test and the CCI model in rats. In CCI rats, this drug prolonged the PWL of the paw affected by nerve injury without altering the PWL of the noninjured paw. These effects were reversed by intrathecal pretreatment with ketanserin in both pain models. Although ketanserin shows a higher affinity for 5-HT2A receptors than 5-HT2C receptors (4), 5-HT2 receptor subtypes that contribute to the antinociceptive effects of -m-5-HT cannot be explained because of the limited selectivity of this antagonist. We selected -m-5-HT as a 5-HT2A/2C receptor agonist because this drug has potent antinociceptive action but does not induce such abnormal behavior as the restlessness associated with another 5-HT2A/2C receptor agonist, (±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) (10). The abnormal behavior induced by DOI may not be attributable to spinal 5-HT2A/2C receptors because it was not reversed by intrathecal pretreatment with ketanserin in our preliminary experiment.
In the present study, -m-5-HT dose-dependently suppressed flinches in both the first and second phases of the formalin test. Formalin injection into the rat hind paw produces biphasic pain-related behavior, such as flinching and licking of the injected paw, providing information about both short-term (acute) and relatively long-term (chronic) nociception. The first phase of behavior in the formalin test is considered to result from direct activation of Aß, A
, and C fibers; the second phase of behavior may involve continuing input from C fibers located at the injection site together with A and C fibers from adjacent sites because these are activated by the spread of inflammation (18). Repetitive C-fiber stimulation is known to induce facilitated discharge of wide dynamic range neurons, a process termed wind-up. This mechanism is also thought to be involved in the second-phase responses (13).
Bennett and Xie (11) reported that a hyperalgesic response to noxious radiant heat was evident in rats by the second postoperative day and lasted for two months after four loose ligatures had been applied unilaterally to the sciatic nerve. It has been suggested that a thermal hyperalgesia is dependent on C fiber, and mechanical allodynia is dependent on larger fibers (19,20) . However, the specific mechanism of this thermal hyperalgesia is not well understood. Transsynaptic changes, degeneration of inhibitory interneurons (21,22) , and abnormal distributions of sodium channels in injured neurons (23) have been reported in this rat neuropathic pain model. Intrathecal administration of morphine increased the thermal response latency of both normal and hyperalgesic paws (24). In contrast, intrathecally administered N-methyl-D-aspartate receptor antagonists specifically attenuated thermal hyperalgesia without altering the response latency of the normal paw (25), suggesting that sensitization of wide dynamic range neurons is important in the mechanism of thermal hyperalgesia. In this study, intrathecally administered -m-5-HT also was effective against thermal hyperalgesia without altering the PWL in the normal paw. Peak effects were always seen at 5 min after -m-5-HT injection in the CCI model. In contrast, the maximum dose of -m-5-HT was effective over 60 min in the formalin test. Although -m-5-HT was effective in both models, quantitative comparison is impossible because of the differences in methods.
The mechanism of the antinociceptive effect of intrathecal -m-5-HT is not clear. Intrathecal administration of another 5-HT2A/2C receptor agonist, DOI, has been found to prolong tail-flick latency (7) and hot-plate latency (8), but controversy persists concerning the action of spinal 5-HT2A/2C receptors. For example, Eide and Hole (26) reported that, in mice, intrathecal administration of DOI (5 to 20 µg) produced a dose-dependent behavioral syndrome consisting of biting or licking the caudal part of the body in combination with reciprocal hind limb scratching. Kjørsvik et al. (27) showed that an intrathecally administered small dose of DOI increased painlike behavioral responses in the rat formalin test. In electrophysiological studies, El-Yassir et al. (28) found that iontophoretically applied DOI has no effect on the firing of dorsal horn neurons. Hori et al. (29) reported that 5-HT2A/2C receptor agonists increased excitatory postsynaptic currents in dorsal horn neurons. Both 5-HT2A and 5-HT2C receptors are coupled to phospholipase C. Accumulation of inositolphosphates and Ca2+ mobilization are involved in the postreceptor events. These observations may indicate that intrathecally delivered 5-HT2A/2C receptor agonists mediate excitatory effects in the central nervous system. We suspect that the antinociceptive effect of -m-5-HT may involve activation of inhibitory interneurons. Antinociceptive effects of intrathecal -m-5-HT were reversed by muscarinic receptor antagonists, suggesting that -m-5-HT may induce ACh release (15). Abi-Saab et al. (16) provided evidence that activation of 5-HT2A/2C receptors increased extracellular GABA in the rat brain. In this study, we demonstrated that atropine reversed the antinociceptive effect of -m-5-HT in both models of sustained pain. GABA receptor antagonists also reversed the antinociceptive effect of -m-5-HT in Phase 1 in the formalin test. In contrast, GABA receptor antagonists did not reverse the antihyperalgesic effect of -m-5-HT in the CCI model. This result is reasonable considering inhibitory neurons including those in GABAergic systems may undergo degeneration or reduction in number in rats with neuropathy (22). However, in the formalin test, GABA may be released in the spinal cord after formalin injection as an intrinsic antinociceptive mechanism (17). Although we selected doses of GABA receptor antagonists that did not affect the baseline number of flinches, the intrinsic inhibitory action of GABA could be modified by the intrathecal administration of the GABA receptor antagonists in Phase 1. In any case, the inhibitory neurotransmitter’s release upon activation of 5-HT2A/2C receptors in the spinal cord could be the basis of the antinociceptive effect of -m-5-HT. Although descending 5-HT systems may tonically inhibit pain transmission in the spinal cord, 30 µg of ketanserin alone did not alter the number of flinches compared with baseline observations in the formalin test or affect PWL in CCI rats. This result suggests that spinal 5-HT2A/2C receptors may not contribute to tonic inhibition of nociceptive transmission. Whereas we did not assess the vascular effect of -m-5-HT, a vasoconstrictive effect mediated by spinal 5-HT2A/2C receptors might have some role in spinal antinociception.
In summary, intrathecal administration of -m-5-HT had an antinociceptive effect in two different rat models of sustained pain. Receptors for 5-HT2A/2C in the dorsal horn of the spinal cord may play a role in inhibition of certain types of chronic pain.
|
Acknowledgments |
|---|
Supported, in part, by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (No. 12671451 and 10470313).
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Yaksh TL, Wilson PR. Spinal serotonin terminal system mediates antinociception. J Pharmacol Exp Ther 1979; 208: 446–53.
[Free Full Text] - Xu W, Qiu XC, Han JS. Serotonin receptor subtypes in spinal antinociception in the rat. J Pharmacol Exp Ther 1994; 269: 1182–9.
[Abstract/Free Full Text] - Bardin L, Bardin M, Lavarenne J, Eschalier A. Effect of intrathecal serotonin on nociception in rats: influence of the pain test used. Exp Brain Res 1997; 113: 81–7.[Web of Science][Medline]
- Hoyer D, Clarke DE, Fozard JR, et al. International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 1994; 46: 157–203.[Abstract]
- Eide PK, Hole K. The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity. Cephalalgia 1993; 13: 75–85.[Web of Science][Medline]
- Pompeiano M, Palacios JM, Mengod G. Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Brain Res Mol Brain Res 1994; 23: 163–78.[Medline]
- Solomon RE, Gebhart GF. Mechanisms of effects of intrathecal serotonin on nociception and blood pressure in rats. J Pharmacol Exp Ther 1988; 245: 905–12.
[Abstract/Free Full Text] - Crisp T, Stafinsky JL, Spanos LJ, et al. Analgesic effects of serotonin and receptor selective serotonin agonists in the rat spinal cord. Gen Pharmacol 1991; 22: 247–51.[Web of Science][Medline]
- Danzebrink RM, Gebhart GF. Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat. Brain Res 1991; 538: 64–75.[Web of Science][Medline]
- Obata H, Saito S, Sasaki M, et al. Antiallodynic effect of intrathecally administered 5-HT2 agonists in rats with nerve ligation. Pain 2001; 90: 173–9.[Web of Science][Medline]
- Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33: 87–107.[Web of Science][Medline]
- Yaksh TL, Rudy TA. Chronic catheterization of spinal subarachnoid space. Physiol Behav 1976; 17: 1031–6.[Medline]
- Yamamoto T, Yaksh T. Comparison of the antinociceptive effects of pre- and posttreatment with intrathecal morphine and MK801, an NMDA antagonist, on the formalin test in the rat. Anesthesiology 1992; 77: 757–63.[Web of Science][Medline]
- Hargreves K, Dubner R, Brown F, et al. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988; 32: 77–88.[Web of Science][Medline]
- Obata H, Saito S, Sasaki M, et al. Possible involvement of a muscarinic receptor in the anti-allodynic action of a 5-HT2 receptor agonist in rats with nerve ligation injury. Brain Res 2002; 932: 124–8.[Web of Science][Medline]
- Abi-Saab WM, Bubser M, Roth RH, et al. 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology 1999; 20: 92–6.[Web of Science][Medline]
- Kaneko M, Hammond DL. Role of -aminobutyric acidA receptors in formalin-induced nociception in the rat. J Pharmacol Exp Ther 1997; 282: 928–38.
[Abstract/Free Full Text] - Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 1995; 64: 345–55.
- Wegert S, Ossipov MH, Nichols ML, et al. Differential activities of intrathecal MK-801 or morphine to alter responses to thermal and mechanical stimuli in normal or nerve-injured rats. Pain 1997; 71: 57–64.[Web of Science][Medline]
- Field MJ, Bramwell S, Hughes J, et al. Detection of static and dynamic component of mechanical allodynia in rat model of neuropathic pain: are they signaled by distinct primary sensory neurons? Pain 1999; 83: 303–11.[Web of Science][Medline]
- Sugimoto T, Bennett GJ, Kajander KC. Transsynaptic degeneration in the superficial dorsal horn after sciatic nerve injury: effects of a chronic constriction injury, transection, and strychnine. Pain 1990; 42: 205–13.[Web of Science][Medline]
- Ibuki T, Hama AT, Wang XT, et al. Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience 1997; 76: 845–58.[Web of Science][Medline]
- Novakovic SD, Tzoumaka E, McGivern JG, et al. Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions. J Neurosci 1998; 18: 2174–87.
[Abstract/Free Full Text] - Yamamoto T, Yaksh T. Studies on the spinal interaction of morphine and NMDA antagonist MK-801 on the hyperesthesia observed in a rat model of sciatic mononeuropathy. Neurosci Lett 1992; 135: 67–70.[Web of Science][Medline]
- Yamamoto T, Yaksh T. Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve: excitatory amino acid antagonists. Pain 1992; 49: 121–8.[Web of Science][Medline]
- Eide PK, Hole K. Different role of 5-HT1A and 5-HT2 receptors in spinal cord in the control of nociceptive responsiveness. Neuropharmacology 1991; 30: 727–31.[Web of Science][Medline]
- Kjørsvik A, Tjølsen A, Hole K. Activation of spinal serotonin2A/2C receptors augments nociceptive responses in the rat. Brain Res 2001; 910: 179–81.[Web of Science][Medline]
- El-Yassir N, Fleetwood-Walker SM, Mitchell R. Heterogeneous effects of serotonin in the dorsal horn of rat: the involvement of 5-HT1 receptor subtypes. Brain Res 1988; 456: 147–58.[Web of Science][Medline]
- Hori Y, Endo K, Takahashi T. Long-lasting synaptic facilitation induced by serotonin in superficial dorsal horn neurons of the rat spinal cord. J Physiol 1996; 492: 867–76.
[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
 |
|
  B. D. Schlag, Z. Lou, M. Fennell, and J. Dunlop Ligand Dependency of 5-Hydroxytryptamine 2C Receptor Internalization J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 865 - 870. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
