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Anesth Analg 2002;95:163-168
© 2002 International Anesthesia Research Society

PAIN MEDICINE

An Investigation of Monoamine Receptors Involved in Antinociceptive Effects of Antidepressants

Fumiko Yokogawa, MD*, Yuji Kiuchi, MD, PhD{dagger}, Yuji Ishikawa, MS{dagger}, Naoki Otsuka, MD, PhD*, Yutaka Masuda, MD, PhD*, Katsuji Oguchi, MD, PhD{ddagger}, and Akiyoshi Hosoyamada, MD, PhD*

*Department of Anesthesiology and {ddagger}First Department of Pharmacology, School of Medicine, and {dagger}Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan

Address correspondence and reprint requests to Fumiko Yokogawa, MD, Department of Anesthesiology, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan. Address e-mail to yokogawa{at}zj8.so-net.ne.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We attempted to determine which monoamine re-ceptor subtypes are predominantly involved in antidepressant-induced antinociception. Antinociceptive effects were evaluated by using formalin tests with rats. Antidepressants acting as potent inhibitors of norepinephrine reuptake (nisoxetine, nortriptyline, and maprotiline) or inhibiting reuptake of both norepinephrine and serotonin (5-HT) (imipramine and milnacipran) induced dose-dependent antinociception. Simultaneous intraperitoneal administration of antidepressants and either prazosin ({alpha}1 antagonist) or ketanserin (5-HT2 antagonist) significantly antagonized antinociceptive effects. Fluvoxamine (selective serotonin reuptake inhibitor) induced antinociception less potently than other antidepressants and was significantly antagonized by ketanserin, but not prazosin. Ondansetron (5-HT3 antagonist) significantly antagonized antinociception by 10 mg/kg of imipramine. In contrast, SDZ-205,557 (5-HT4 antagonist) markedly enhanced antinociception by small-dose (2.5 mg/kg) imipramine. Imipramine-induced antinociception was significantly antagonized by intracerebroventricular administration of prazosin or ketanserin, but not by yohimbine ({alpha}2 antagonist) or ondansetron, and was significantly enhanced by intracerebroventricularly administered SDZ-205,557. These findings suggest that {alpha}1 adrenoceptors and 5-HT2 receptors in the brain are involved in antidepressant-induced antinociception. In addition, the results suggested functional interactions between noradrenergic and serotonergic neurons as mechanisms for antidepressant-induced antinociception.

IMPLICATIONS: Formalin tests of rats treated with antidepressants and antagonists of monoamine receptors indicate that {alpha}1 adrenoceptors, serotonin (5-HT)2 receptors, and 5-HT3 receptors are involved in antidepressant-induced antinociception, suggesting functional interactions between noradrenergic and serotonergic neurons as mechanisms of antidepressant-induced antinociception.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Antidepressants have antinociceptive effects in addition to antidepressant activity (1–3). Although thorough comparisons of the antinociceptive potencies of clinically used antidepressants have not been conducted, our previous study (with formalin tests in rats) suggested that classic tricyclic antidepressants exert more potent antinociceptive effects than selective serotonin reuptake inhibitors (SSRIs) (4).

The neurochemical mechanisms of antinociceptive effects of antidepressants have not been well described. Most antidepressants inhibit the reuptake of monoamines, including norepinephrine and serotonin (5-HT), at neuronal terminals (5). Increased levels of monoamines in synaptic clefts are therefore presumed to lead to changes in pain thresholds and induce antinociception. However, there is still controversy over the identity of the monoamine receptors (or receptor subtypes) responsible for these analgesic effects, in addition to their location (central or peripheral) (6,7).

Thus, in this study, by using the formalin test in rats, we attempted to determine the identity and possible localization of the monoamine receptor subtypes ({alpha}1,2 and 5-HT2,3,4) predominantly involved in the antinociceptive effects of antidepressants, by investigating antagonism of antidepressant-induced antinociception after peripheral or central administration of specific receptor antagonists. In addition, we propose a possible mechanism for interactions between the noradrenergic and serotonergic systems involved in antidepressant-induced antinociception.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
We used 380 male Wistar rats (Japan SLC, Hamamatsu, Japan) weighing 180 to 245 g. The rats were housed in groups of four to six animals at 20°C to 24°C, in a humidity-controlled room under a 12:12-h light/dark cycle (lights on at 6:00 AM and off at 6:00 PM). The rats were supplied food and water ad libitum and were given at least 3 days to adapt to the animal room before being tested. The ambient temperature during testing was 20°C to 24°C. The animals were brought to the test room at least 1 h before testing. Each rat was used for only one experiment. All procedures were in strict accordance with the National Institutes of Health’s guidelines for the care and use of laboratory animals and were approved by our Animal Care and Use Committee.

The antinociceptive effects of antidepressants were evaluated by using formalin tests in rats. Sixty minutes before formalin injection, animals were intraperitoneally (IP) administered an antidepressant (2 mL/kg) with or without simultaneous administration of a monoamine receptor antagonist. Fifty microliters of formalin solution (2% in water) was injected subcutaneously into the plantar surface of the right hind paw with a 27-gauge needle. The animal was then immediately placed into an open Plexiglas box (30 x 30 x 34 cm) serving as the observation chamber. Rats usually lick the injected paw in two phases: immediately after injection (early phase) and approximately 20 min after injection (late phase). We measured the total time (in seconds) that the animal spent licking the injected paw during the period lasting from 10 to 30 min after formalin injection (late phase).

Each rat was gently placed into the center of a Plexiglas box (30 x 30 x 34 cm) 60 min after IP administration of an antidepressant. The number of line crossings (lines dividing the floor into nine parts) was then counted for 15 min and used as ambulatory locomotor activity data.

Two days before the experiment, the animal was anesthetized with an IP administration of pentobarbital sodium (50 mg/kg) and placed onto a stereotaxic instrument (Narishige Scientific Instrument Laboratory, Tokyo, Japan). Stainless-steel 27-gauge guide cannulae were then aseptically implanted in bilateral hemispheres of the cerebral cortex. The lower tip of each cannula was positioned 2.0 mm from the center of each lateral ventricle (distance from the bregma: anterior, -1.0 mm; lateral, ±1.5 mm; vertical, +2.0 mm) (8). On the day of the experiment, 60 min before the formalin injection, animals underwent IP administration of an antidepressant, and injection needles (outer diameter, 0.2 mm; inner diameter, 0.08 mm) were inserted through the guide cannulae into both lateral ventricles (2.0 mm beyond the guide cannula) 40 min after antidepressant administration. A monoamine receptor antagonist or saline (control) was administered into both lateral ventricles at a rate of 1.0 µL/min for 5 min (total volume for both ventricles, 10 µL) through the injection needles by using a microsyringe pump (EP-60; EICOM, Tokyo, Japan). After the injection needles were removed, the formalin test was performed as described previously. Accurate placement of the cannulae was visually confirmed after the experiment by checking the diffusion of blue ink injected into the ventricles.

The following antidepressants were used: nortriptyline HCl, nisoxetine HCl, maprotiline HCl, and imipramine HCl (Sigma, St. Louis, MO); milnacipran HCl (donated by Asahikasei Corp., Osaka, Japan); fluvoxamine maleate (donated by Solvay Pharmaceutical, Weesp, The Netherlands); and citalopram HBr (donated by Zeria Pharmaceutical, Tokyo, Japan). The following selective {alpha}-adrenergic or serotonergic receptor antagonists were used: prazosin HCl and yohimbine HCl (Sigma); ketanserin tartrate (RBI, Natick, MA); ondansetron HCl (donated by Glaxo Wellcome, Tokyo, Japan); and SDZ-205,557 (RBI). The dosages of all antagonists used in this study were chosen to selectively block a corresponding receptor, on the basis of data from published in vivo studies (9–11). We randomized the assignments of drugs and dosages among the rats.

Results are expressed as mean ± SEM. The statistical significance of differences between experimental data was analyzed with analysis of variance, followed by the Sheffé post hoc test. Values of P < 0.05 were considered indicative of statistical significance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Table 1 shows the results of formalin tests for the antinociceptive effects of antidepressants. All the SSRIs (nortriptyline, nisoxetine, and maprotiline) and the drugs inhibiting both norepinephrine and 5-HT reuptake (imipramine and milnacipran) produced significant dose-dependent reductions in the time spent by the rats licking the injected paw. Antinociceptive effects were observed for nisoxetine at doses larger than 2.5 mg/kg; for nortriptyline, imipramine, and milnacipran at doses larger than 5 mg/kg; and for maprotiline at doses larger than 10 mg/kg. At 20 mg/kg, nortriptyline, nisoxetine, and imipramine nearly abolished the formalin-induced nociceptive response (86.3%, 96.2%, and 95.1% reduction of licking time, respectively).


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  		Table 1. Antinociceptive Activity of Antidepressants After Single Intraperitoneal Administration in the Formalin Test
 
In the open field test, apparent inhibition of ambulatory activity was not observed after IP administration of nortriptyline (5 mg/kg), nisoxetine (2.5 mg/kg), maprotiline (10 mg/kg), imipramine (5 mg/kg), milnacipran (5 mg/kg), or fluvoxamine (20 mg/kg). These are the minimal doses that induce significant differences in formalin-induced nociception (data not shown).

Figure 1A shows the effects of the {alpha}1-receptor antagonist prazosin and the 5-HT2 antagonist ketanserin on antinociception induced by the selective norepinephrine reuptake inhibitors nortriptyline (5 mg/kg), nisoxetine (2.5 mg/kg), and maprotiline (10 mg/kg), as indicated by the formalin test. Pretreatment with prazosin (1 mg/kg) and ketanserin (1 mg/kg) significantly and almost completely antagonized the suppression of licking time. Licking time was increased by the following amounts: nortriptyline, from 60.6 to 136.6 and 137.0 s; nisoxetine, from 54.8 to 153.0 and 119.2 s; and maprotiline, from 59.1 to 122.9 and 148.4 s for prazosin and ketanserin, respectively.



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  		Figure 1. Effects of monoamine receptor antagonists on antinociception induced by (A) selective inhibitors of norepinephrine reuptake and by (B) serotonin and norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors in the formalin test. Nortriptyline (5 mg/kg), nisoxetine (2.5 mg/kg), maprotiline (10 mg/kg), milnacipran (5 mg/kg), or fluvoxamine (20 mg/kg) was intraperitoneally administered alone (-) or coadministered with the {alpha}1 antagonist prazosin (P) (1 mg/kg) or the serotonin 2 antagonist ketanserin (K) (with fluvoxamine, 2 mg/kg; with other antidepressants, 1 mg/kg). Mean + SEM (n = 7 for each column). aP < 0.01 versus saline; bP < 0.05 versus antidepressant alone; cP < 0.01 versus antidepressant alone.

 
Figure 1B shows the effects of pretreatment with prazosin and ketanserin on the antinociception induced by the 5-HT and norepinephrine reuptake inhibitor milnacipran (5 mg/kg) and the SSRI fluvoxamine (20 mg/kg). Both prazosin and ketanserin significantly antagonized milnacipran-induced suppression of licking time: the time increased from 78.3 to 150.9 and 136.4 s, respectively. The antinociceptive effect of fluvoxamine was not altered by prazosin, but ketanserin significantly antagonized the suppression of licking time, increasing licking time from 67.3 to 121.7 s.

The effects of antagonists of 5-HT3 and 5-HT4 re-ceptors on imipramine-induced antinociception, as shown by the formalin test, are shown in Figure 2. Pretreatment with the 5-HT3 antagonist ondansetron (1 mg/kg) significantly antagonized suppression of licking time by imipramine (10 mg/kg), increasing licking time from 7.3 to 125.3 s. In contrast, pretreatment with the 5-HT4 antagonist SDZ-205,557 (0.1 mg/kg) significantly enhanced reduction of licking time by a small dose of imipramine (2.5 mg/kg), decreasing licking time from 111.0 to 15.6 s. None of the antagonists—prazosin (1 mg/kg), ketanserin (1 and 2 mg/kg), ondansetron (1 mg/kg), or SDZ-205,557 (0.1 mg/kg)—exerted statistically significant effects on the formalin test when administered singly without an antidepressant (data not shown).



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  		Figure 2. Effects of serotonin (5-HT)3 and 5-HT4 receptor antagonists on imipramine-induced antinociception in the formalin test. Imipramine (10 mg/kg) was intraperitoneally administered alone (-) or coadministered with the 5-HT3 antagonist ondansetron (OND) (1 mg/kg). A small dose of imipramine (2.5 mg/kg) was intraperitoneally administered alone (-) or coadministered with the 5-HT4 antagonist SDZ-205,557 (SDZ) (0.1 mg/kg). Mean + SEM (n = 7 for each column). aP < 0.01 versus saline; bP < 0.01 versus imipramine alone.

 
Figure 3 shows the effects of intracerebroventricular (ICV) administration of monoamine receptor antagonists on imipramine-induced antinociception, as shown by the formalin test. Prazosin (5 µg) and ketanserin (60 µg) significantly antagonized imipramine-induced suppression of licking time, increasing licking time from 48.0 to 103.4 s and from 19.4 to 122.8 s, respectively. The antinociceptive effect of imipramine was not altered by the {alpha}2 antagonists yohimbine (60 µg) or ondansetron (60 µg). In contrast, ICV injection of SDZ-205,557 (1 µg) markedly enhanced the slight reduction in licking time induced by a small dose of imipramine (1.25 mg/kg), decreasing licking time from 139.4 to 16.0 s. Neither antagonist by itself significantly affected licking time in the formalin test when administered ICV at the dose indicated previously without concomitant administration of an antidepressant (data not shown).



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  		Figure 3. Effect of intracerebroventricular (ICV) administration of monoamine receptor antagonists on the antinociception induced by intraperitoneally administered imipramine in the formalin test. Imipramine 1.25, 5, or 10 mg/kg was administered intraperitoneally and was followed by ICV administration of the {alpha}1 antagonist prazosin (P) 5 µg, the {alpha}2 antagonist yohimbine (Y) 60 µg, the 5-HT3 antagonist ondansetron (OND) 60 µg, the serotonin (5-HT)2 antagonist ketanserin (K) 60 µg, the 5-HT4 antagonist SDZ-205,557 (SZD) 1 µg, or saline (-). Mean + SEM (n = 5 each). aP < 0.05 versus saline; bP < 0.01 versus saline; cP < 0.05 versus imipramine alone; dP < 0.01 versus imipramine alone.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study and previous studies (4) demonstrated that antidepressants selectively inhibiting reuptake of norepinephrine only (nortriptyline, nisoxetine, and maprotiline) or 5-HT only (SSRIs; fluvoxamine and citalopram) or inhibiting the reuptake of both norepinephrine and 5-HT (imipramine and milnacipran) could all induce antinociception. SSRIs demonstrated this effect to a lesser extent than other antidepressants. Antidepressants increase monoamine levels in synaptic clefts by inhibiting the reuptake of monoamines into nerve terminals, resulting in increased stimulation of monoamine receptors. It has thus been assumed that certain subtypes of monoamine receptors are involved in antidepressant-induced antinociception. The antinociceptive potency of selective inhibitors of norepinephrine reuptake was greatest in nisoxetine, followed by nortriptyline and maprotiline. This seems to be comparable with reported in vitro Ki values for the inhibition of norepinephrine uptake (1.3, 4.0, and 7.4 nM, respectively) (5). These findings are likely to support the involvement of stimulation of monoamine receptors in antidepressant-induced antinociception. In contrast to our study, Jourdan et al. (12) have reported that nortriptyline did not significantly affect the pain score during formalin tests in rats. The reasons for the discrepancy between their findings and ours are not clear. However, the large concentration of formalin (5%) used in their study compared with that in ours (2%) might have elicited pain too intense to be antagonized by nortriptyline.

The antinociceptive effects of nortriptyline, nisoxetine, maprotiline, and milnacipran (in this study) and of imipramine (4) are significantly and markedly antagonized by the {alpha}1 antagonist prazosin and the 5-HT2 antagonist ketanserin. In the previous study (4), the selective {alpha}1A antagonist WB-4101 also significantly inhibited imipramine-induced antinociception, supporting the possibility of {alpha}1-receptor involvement in antinociception by antidepressants. In addition, the antinociceptive effects of imipramine in this study were markedly antagonized by the 5-HT3 antagonist ondansetron. In contrast, the 5-HT4 antagonist SDZ-205,557 induced significant antinociception, but only when coadministered with a small dose of imipramine. These results suggest that the {alpha}1 adrenoceptors and the 5-HT2 and 5-HT3 receptors are involved in the antinociception induced by antidepressants and that stimulation of the 5-HT4 receptors antagonizes or buffers this antinociception (Table 2). Stimulation of the 5-HT4 receptors might be one of reasons why SSRIs demonstrate less antinociceptive activity than classic antidepressants. In our previous study using the same experimental method as this study, we found that the antinociceptive effects of imipramine during the formalin test in rats were not significantly affected by either the IP-administered {alpha}2 antagonist yohimbine or the 5-HT1A antagonist WAY-100,635 (4). This suggests that participation of the {alpha}2 adrenoceptors and the 5-HT1A receptors in antidepressant-induced antinociception either is not obvious or is less dominant than that of the {alpha}1 adrenoceptors and the 5-HT2 and 5-HT3 receptors (Table 2).


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  		Table 2. Possible Involvement of Central and Peripheral Monoamine Receptors in the Antinociceptive Effect of Antidepressants
 
Several previous reports support our findings regarding the contributions of monoamine receptors to antidepressant-induced antinociception. Ansuategui et al. (13) found that the antinociceptive effects of clomipramine were closely related to {alpha}1 adrenoceptors, but not {alpha}2 adrenoceptors. Walker et al. (14) reported that the 5-HT2 antagonists pirenperone and ritanserin reduced naloxone-induced antinociception. It has also been demonstrated that ondansetron attenuates the antinociceptive effect of nifedipine, an L-type calcium channel blocker, in rats (10) and that SDZ-205,557 antagonizes visceral and cutaneous pain in mice (11).

However, in contrast to our findings, some articles have indicated that either 5-HT1A or 5-HT3 receptors are involved in 5-HT-induced pain (15,16). In addition, clonidine, an {alpha}2 agonist, is effective in relieving neuropathic and cancer pain (17,18). The reasons for the discrepancies between our findings and these studies are unclear. One possible explanation is that the involvement of these monoamine receptor subtypes in the regulation of pain under conditions in which monoamine levels in synaptic clefts have been markedly increased by antidepressants is different from that under normal, stable conditions in the absence of antidepressants. However, Ghelardini et al. (19) and Sahebgharani and Zarrindast (20) reported that {alpha}2 adrenoceptors were likely to be involved in antidepressant-dependent antinociception in mice. The discrepancy between their findings and ours might be partly attributable to differences in experimental conditions, such as the quality of the noxious stimulus and the species (the formalin test in rats in our study versus the hot-plate test and the writhing test in mice in their studies).

Because IP-administered antagonists can block monoamine receptors in both the central nervous system and local peripheral regions, we were unable to localize the receptors involved in antidepressant-induced antinociception. Therefore, we instead investigated the involvement of receptors in the brain in the antinociceptive effects of imipramine, by using ICV administration of antagonists. The antinociceptive effects of imipramine were significantly antagonized by prazosin and ketanserin but were not affected by yohimbine or ondansetron. In contrast, the antinociceptive effects of imipramine were significantly and markedly enhanced by SDZ-205,557. These findings suggest that the {alpha}1 adrenoceptors and the 5-HT2 and 5-HT4 receptors, which are involved in the antinociceptive effects of imipramine, are at least partially localized in the brain (Table 2). This conclusion is supported by findings indicating that ICV pretreatment with prazosin prevents the induction of antinociception by ICV administration of norepinephrine (21) and that ICV pretreatment with ketanserin inhibits antinociception induced by calcitonin (22). Asano et al. (23) also suggested that {alpha}1 adrenoceptors may participate in pain control at the supraspinal level. In this study, IP administration of ondansetron significantly antagonized the antinociception induced by imipramine, but ICV administration of ondansetron did not. However, the involvement of central 5-HT3 receptors in the antinociceptive effect of imipramine could not be excluded; concentrations of the antagonist might not reach effective levels at the site of action of imipramine in the brain, because of dilution. Bardin et al. (24) reported that intrathecal pretreatment with the 5-HT3 antagonist tropisetron reversed the antinociception induced by intrathecally administered 5-HT. Thus, further experiments are needed to determine whether central 5-HT3 receptors might contribute to the antinociceptive effect of antidepressants.

In this investigation, the antinociceptive effects of antidepressants that selectively inhibit norepinephrine reuptake (nortriptyline, nisoxetine, and maprotiline) were significantly and markedly antagonized by 5-HT2 antagonists. This suggests that, in antidepressant-related antinociception, noradrenergic neurons interact with serotonergic neurons. In addition, the antinociceptive effects of the SSRI fluvoxamine in this study were antagonized by the 5-HT2 antagonist but were not affected by the {alpha}1 antagonist. From these findings, we speculated possible neuronal interactions at the supraspinal level, in which noradrenergic neurons innervate serotonergic neurons presynaptically and presynaptic {alpha}1 receptors stimulate 5-HT secretion. Plaznik et al. (25) suggested a functional interaction between noradrenergic and serotonergic systems in rats and demonstrated that norepinephrine released from noradrenergic terminals in the median raphe nucleus regulates the activity of 5-HT. However, morphological evidence for interactions among noradrenergic neurons, serotonergic neurons, and 5-HT receptor subtypes has not yet been adequately demonstrated. Further pharmacological and anatomical investigations are therefore necessary to elucidate the mechanisms involved in antidepressant-induced antinociception.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Gray AM, Pache DM, Sewell RD. Do alpha2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds? Eur J Pharmacol 1999; 378: 161–8.[Web of Science][Medline]
  2. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain 1992; 49: 205–19.[Web of Science][Medline]
  3. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999; 83: 389–400.[Web of Science][Medline]
  4. Otsuka N, Kiuchi Y, Yokogawa F, et al. Antinociceptive efficacy of antidepressants: assessment of five antidepressants and four monoamine receptors in rats. J Anesth 2001; 15: 154–8.[Medline]
  5. Richelson E, Pfenning M. Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol 1984; 104: 277–86.[Web of Science][Medline]
  6. Korzeniewska-Rybicka I, Plaznik A. Analgesic effect of antidepressant drugs. Pharmacol Biochem Behav 1998; 59: 331–8.[Web of Science][Medline]
  7. Tura B, Tura SM. The analgesic effect of tricyclic antidepressants. Brain Res 1990; 518: 19–22.[Medline]
  8. Kurato T, Kiuchi Y, Yasuhara H, et al. N-Methyl-D-aspartate receptor agonists and antagonists partially affect the duration of ketamine anesthesia in the rat. J Anesth 1995; 9: 243–6.
  9. Schreiber R, Melon C, De Vry J. The role of 5-HT receptor subtypes in the anxiolytic effect of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test. Psychopharmacology 1998; 135: 383–91.[Medline]
  10. Hunt TE, Wu W, Zbuzek VK. Ondansetron blocks nifedipine-induced analgesia in rats. Anesth Analg 1996; 82: 498–500.[Abstract]
  11. Espejo EF, Gil E. Antagonism of peripheral 5-HT4 receptors reduces visceral and cutaneous pain in mice, and induces visceral analgesia after simultaneous inactivation of 5-HT3 receptors. Brain Res 1998; 788: 20–4.[Medline]
  12. Jourdan D, Alloui A, Eschalier A. Pharmacological validation of an automated method of pain scoring in the formalin test in rats. J Pharmacol Toxicol 1999; 42: 163–70.
  13. Ansuategui M, Naharro L, Feria M. Noradrenergic and opioidergic influences on the antinociceptive effect of clomipramine in the formalin test in rats. Psychopharmacology 1989; 98: 93–6.[Medline]
  14. Walker MJ, Poulos CX, Le AD. Effects of acute selective 5-HT1, 5-HT2, 5-HT3 receptor and alpha 2 adrenoceptor blockade on naloxone-induced antinociception. Psychopharmacology (Berl) 1994;113:527–33.
  15. Taiwo YO, Levine JD. Serotonin is a directly-acting hyperalgesic agent in the rat. Neuroscience 1992; 48: 485–90.[Web of Science][Medline]
  16. Eschalier A, Kayser V, Guilbaud G. Influence of a specific 5-HT3 antagonist on carrageenan-induced hyperalgesia in rats. Pain 1989; 36: 249–55.[Web of Science][Medline]
  17. Davis KD, Treede RD, Raja SN, et al. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain 1991; 47: 309–17.[Web of Science][Medline]
  18. Eisenach JC, Du Pen S, Dubois M, et al. Epidural clonidine analgesia for intractable cancer pain: the Epidural Clonidine Study Group. Pain 1995; 61: 391–9.[Web of Science][Medline]
  19. Ghelardini C, Galeotti N, Bartolini A. Antinociception induced by amitriptyline and imipramine is mediated by {alpha}2A-adrenoceptors. Jpn J Pharmacol 2000; 82: 130–7.[Medline]
  20. Sahebgharani M, Zarrindast MR. Effect of {alpha}-adrenoceptor agents on imipramine-induced antinociception in nerve-ligated mice. Eur Neuropsychopharmacol 2001; 11: 99–104.[Medline]
  21. Zhang C, Guo YQ, Qiao JT, Dafny N. Locus coeruleus modulates thalamic nociceptive responses via adrenoceptors. Brain Res 1998; 784: 116–22.[Web of Science][Medline]
  22. Yamazaki N, Umeno H, Kuraishi Y. Involvement of brain serotonergic terminals in the antinociceptive action of peripherally applied calcitonin. Jpn J Pharmacol 1999; 81: 367–74.[Medline]
  23. Asano T, Dohi S, Ohta S, et al. Antinociception by epidural and systemic {alpha}2-adrenoceptor agonists and their binding affinity in rat spinal cord and brain. Anesth Analg 2000; 90: 400–7.[Abstract/Free Full Text]
  24. Bardin L, Lavarenne J, Eschalier A. Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats. Pain 2000; 86: 11–8.[Web of Science][Medline]
  25. Plaznik A, Danysz W, Kostowski W, et al. Interaction between noradrenergic and serotonergic brain systems as evidenced by behavioral and biochemical effects of microinjections of adrenergic agonists and antagonists into the median raphe nucleus. Pharmacol Biochem Behav 1983; 19: 27–32.[Medline]
Accepted for publication March 27, 2002.




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H. Obata, S. Saito, S. Koizuka, K. Nishikawa, and F. Goto
The Monoamine-Mediated Antiallodynic Effects of Intrathecally Administered Milnacipran, a Serotonin Noradrenaline Reuptake Inhibitor, in a Rat Model of Neuropathic Pain
Anesth. Analg., May 1, 2005; 100(5): 1406 - 1410.
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S.-W. Shin, J. C. Eisenach, S. G. Rao, and C. Tong
The Monoamine Reuptake Inhibitor Milnacipran Does Not Affect Nociception to Acute Visceral Distension in Rats
Anesth. Analg., May 1, 2004; 98(5): 1365 - 1369.
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F. Marchand, D. Ardid, E. Chapuy, A. Alloui, D. Jourdan, and A. Eschalier
Evidence for an Involvement of Supraspinal {delta}- and Spinal {micro}-Opioid Receptors in the Antihyperalgesic Effect of Chronically Administered Clomipramine in Mononeuropathic Rats
J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 268 - 274.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press