Possible involvement of opioidergic and serotonergic mechanisms in antinociceptive effect of paroxetine in acute pain

Antidepressant drugs, especially tricyclics have been widely used in the treatment of chronic pain, but not in acute pain. Because of numerous undesirable side effects, the selective serotonin reuptake inhibitors (SSRIs), with their favorable side effect profile, are preferred nowadays. An activation of the endogenous opioid mechanisms or potentiation of the analgesic effect mediated by serotonergic and/or noradrenergic pathways are thought to be involved in the antinociceptive action of SSRIs. In this study, the potential antinociceptive effect of paroxetine and its interaction with opioidergic system and serotonin receptors were evaluated. The antinociceptive effect of paroxetine was tested using a hot plate test in mice. Paroxetine, a SSRI antidepressant drug, induced an antinociceptive effect following i.p. administration. This antinociception was significantly inhibited by naloxone, an opioid receptor antagonist, suggesting the involvement of opioidergic mechanisms. While ondansetron (a 5-HT(3)-receptor antagonist) inhibited the effect of paroxetine, ketanserin (a 5-HT(2)-receptor antagonist) could not. In conclusion, paroxetine-induced antinociception, similar to morphine, suggests an involvement of direct or indirect action (via an increase in release of endogenous opioid peptide(s)) at opioid receptor sites and an involvement of serotonergic mechanisms mainly at the receptor level.     

Effect of chronic treatment with tricyclic antidepressants upon antinociception induced by intrathecal injection of morphine and monoamines

The effects of acute and chronic treatment with tricyclic antidepressants (TCA) upon antinociception induced by intrathecally administered serotonin (5-HT), norepinephrine (NE), and morphine were assessed at weekly intervals by the tail-flick method in the rat. Acute pretreatment with either clomipramine (28.5 mumol/kg, s.c.) or desipramine (85.5 mumol/kg, s.c.) enhanced the analgesia induced by both intrathecally-administered morphine (7.5 nmol) and 5-HT (241 nmol), compared to saline (1 ml/kg) but only desipramine facilitated the effects of intrathecally administered NE (0.49 nmol). The chronic (22 day) administration of both tricyclic antidepressants resulted in loss of the enhancement of the effects of morphine (day 22) and 5-HT (day 15); only desipramine (day 15) abolished the facilitation of NE. In a similar study, acute pretreatment with the non-tricyclic antidepressant inhibitor of the reuptake of NE, nisoxetine, (97.5 mumol/kg, s.c.), amplified the effects of intrathecally administered NE and morphine but not 5-HT-induced analgesia. Although chronic (22 day) treatment with nisoxetine caused a loss of the effects of enhancement of morphine (day 8), there was no effect upon the action of NE and antinociception induced by 5-HT was facilitated (day 22). Receptor binding studies indicated that chronic (22 day) treatment with clomipramine, desipramine or nisoxetine reduced the affinity of opiate [3H]naloxone) receptors in the spinal cord. These results demonstrate that (1) acute treatment with trycyclic antidepressants enhanced analgesia induced by intrathecally injected morphine, and (2) the chronic administration of trycyclic antidepressants resulted in a loss of enhancement of the effects of morphine, given intrathecally, which appeared to be independent of alterations in the activity of NE or 5-HT but may be associated with the development of subsensitive opiate receptors.     

The effect of fluoxetine on morphine analgesia,respiratory depression,and lethality

The analgesic effect of morphine in a mouse writhing assay was enhanced by the simultaneous administration of fluoxetine, an inhibitor of serotonin uptake. Fluoxetine reduced the ED₅₀ for morphine and extended the duration of morphine analgesia. The potentiation of morphine analgesia was particularly striking in mice made tolerant by repeated morphine injections. Potentiation of morphine by fluoxetine was also observed in a rat tail jerk test for analgesia. The acute lethality of morphine in rats and mice was altered by fluoxetine, yet the therapeutic index of morphine (ratio of LD₅₀ to ED₅₀) was unchanged. The decrease in blood pO₂ produced by morphine at doses of 1 and 4 mg/kg in rats was attenuated by fluoxetine, which by itself increased blood pO₂. These findings strengthen earlier evidence for an involvement of serotoninergic neurons in the analgesic effects of morphine and support the idea that enhanced serotoninergic function might be a useful means of enhancing morphine's actions in clinical therapy.     

Supraspinally administered agmatine prevents the development of supraspinal morphine analgesic tolerance

We have determined the effect of intracerebroventricularly (i.c.v.) administered decarboxylated arginine (agmatine) on supraspinally induced chronic morphine analgesic tolerance. Mice pre-treated with a schedule of chronic i.c.v administration of morphine (10 nmol, b.i.d. 3 days) show a 12-fold reduction in the potency of acutely administered i.c.v morphine compared to saline injected controls. Co-administration of agmatine (10 nmol) with one of the two daily morphine injections completely prevents the reduction in i.c.v morphine analgesia. Mice injected with agmatine once daily (but no morphine) do not show a increase in morphine analgesic potency relative to saline controls, indicating that a mere potentiation of acute morphine analgesia cannot account for the agmatine-mediated anti-tolerance effect in those mice subjected to the morphine tolerance induction schedule. These observations agree with previous reports that systemically and intrathecally administered agmatine prevent opioid tolerance, and extend these results to include a supraspinal site of action.     

Salmon calcitonin potentiates the analgesia induced by antidepressants

Antidepressants are used in the treatment of a variety of pain syndromes. Most of them act by blocking noradrenaline (NA) and serotonin (5-HT) reuptake. It is also well known that the serotonergic system is also involved in calcitonin (CT) analgesia. Taking these two evidences into account, the modification of the analgesic effect of nortriptyline, amitriptyline, and paroxetine in the presence of salmon CT (s-CT) was examined in mice. The forced-swimming test was carried out in order to choose doses of each drug that did not induce an antidepressant effect under our experimental conditions (nortriptyline: 0.2-5 mg/kg ip, amitriptyline: 2.5-20 mg/kg ip, and paroxetine: 5-30 mg/kg ip). The analgesic effect of each antidepressant was then evaluated using the acetic acid test. At the doses tested, the antidepressants induced a dose-dependent analgesic effect. When mice were pre-treated with a subanalgesic dose of s-CT (2.5 IU/kg), the analgesic effect of amitriptyline and paroxetine was significantly increased though no modification was found for nortriptyline. In summary, s-CT was able to increase the analgesic effect of the antidepressant drugs that reduce the uptake of 5-HT, suggesting that the joint administration of antidepressants and CT may be an interesting alternative in pain management.     

Chronic desipramine attenuates morphine analgesia

Two experiments were conducted to explore the effects of chronic antidepressant treatment on endogenous opioid systems. In the first study, mice received desipramine for 21 days, a regimen which down-regulates beta-adrenergic receptors [13]. Subsequently, hotplate jump latencies were measured after acute saline, morphine or naloxone, to test for dynamic changes in endogenous opioid systems. Chronic desipramine treatment resulted in a significant attenuation of morphine analgesia, but had no effect on latencies of saline and naloxone treated mice. In the second experiment, naltrexone or propranolol were given with desipramine for 21 days, in an attempt to block the development of subsensitivity to morphine. Naltrexone had no effect on desipramine attenuation of morphine analgesia. Propranolol given with desipramine slightly lowered jump latencies of acute saline controls, resulting in a significant analgetic effect of morphine. These data suggest that attenuation of morphine analgesia by chronic desipramine treatment may be mediated by actions on noradrenergic systems, rather than direct effects on opioid receptors.     

Influence of prazosin and clonidine on morphine analgesia,tolerance and withdrawal in mice

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (₂-adrenoceptor agonist) and prazosin (₁-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another ₁-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of ₂-adrenoceptors in opioid actions, also ₁-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.     

Celecoxib induces tolerance in a model of peripheral inflammatory pain in rats

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2). Like most NSAIDs, celecoxib exhibits analgesic effects in models of inflammatory pain but these appear to be dependent on endogenous opioid release. Therefore, this study has assessed the ability of celecoxib to induce tolerance in rats, comparable to that induced by morphine.Rats were injected subcutaneously (s.c.) twice daily with divided doses of celecoxib, morphine or indomethacin. Inflammation was induced in one hind paw of rats by injecting prostaglandin E₂ (PGE₂; 200 ng) 30 min after drug administration, on days 1, 3, 5 and 6 or 7. Nociceptive thresholds to mechanical stimulation were measured 3 h after PGE₂ injection, on the same days. On days 6 or 7, analgesic effects of the full doses of test drugs were assessed.Celecoxib-induced tolerance, as did morphine, an effect not shown by another NSAID, indomethacin. Cross-tolerance between celecoxib and morphine was observed as they did not induce analgesia when animals were chronically treated with morphine or celecoxib, respectively. In addition, tolerance to celecoxib’s analgesic effects persisted for at least two days after the end of the chronic treatment with celecoxib. Naltrexone prevented induction of tolerance to morphine or celecoxib.The present results strengthen the possibility that celecoxib has also mechanisms of analgesia unrelated to COX inhibition but dependent on endogenous opioid release. Our results also imply the existence of a new class of analgesics without the deleterious effects of COX inhibitors.     

Prolonged analgesia induced by cathinone. The role of stress and opioid and nonopioid mechanisms

Cathinone, the active principle of Catha edulis (khat), shows long-lasting analgesic effects when the tail-flick test is used in rats. The involvement of monoamines, endogenous opioids and stress in this analgesic effect was tested. Both early (30 min) and late (24 h) analgesic effects of cathinone were prevented by reserpine or p-chlorophenylalanine, which deplete catecholamines or serotonin, respectively, and by nomifensine, which prevents neuronal uptake of biogenic amines and amphetamines. The same inhibitory effect was obtained with a high dose (4 mg/kg) of naloxone. However, rats made tolerant to morphine retained both early and late analgesic response to cathinone. The increase in plasma ACTH induced by the tail-flick test at 30 min and 24 h was significantly enhanced by cathinone, in a naloxone-reversible way. However, the analgesic responses shown at these times were not prevented by either dexamethasone or adrenalectomy. We conclude that the prolonged analgesia induced by cathinone is primarily due to an amphetamine-like activation of monoaminergic pathways, but requires the integrity of non-mu-opioid mechanisms. The involvement of the adrenohypophyseal axis in this cathinone effect is less probable.     

Tricyclic antidepressant plasma levels after augmentation with citalopram: a case study

Summary In a depressed patient, the addition of citalopram 40–60 mg per day to treatment with amitriptyline 75 mg per day had no effect on the plasma levels of amitriptyline and nortriptyline, but it led to clinical improvement without the appearance of adverse effects.This and similar findings in four other patients comedicated with citalopram and amitriptyline (2 patients), clomipramine or maprotiline suggest that citalopram differs from other selective serotonin reuptake inhibitors, such as fluvoxamine and fluoxetine, which have been shown to increase tricyclic antidepressant plasma levels.     

Blockade of the development of analgesic tolerance to morphine by concurrent treatment with opioid- but not non-opioid-mediated stress in mice

Studies have been carried out to determine how the analgesic effect of morphine and the development of tolerance to the effect would be influenced by concurrent exposure to stresses in mice. Application of footshock (FS) stress, which produces analgesia mediated by opioid mu-receptors, or psychological (PSY) stress, which produces analgesia in a manner more closely related to opioid kappa-receptors, did not affect the analgesic effect of morphine, but completely blocked the development of tolerance during 5 daily concomitant treatments. On the other hand, forced swimming (SW) stress induced analgesia (SIA), which was not antagonized by naloxone, suppressed morphine analgesia, but failed to block the tolerance development. The blockade of the development of tolerance to morphine analgesia by stresses may not be attributed to the analgesic effect induced by the stresses because a combination of weak FS stress, which induces no analgesia, also effectively suppressed the development of morphine tolerance. In addition to the opioid mechanism, an adrenergic mechanism can not be excluded because of the reserpine antagonism of these SIAs.     

Des-tyrosine-γ-endorphin effects on morphine analgesia in mice

• 1.1. The effects that were induced by a β-lipotropin fragment des-tyrosine-γ-endorphin (DTγE) devoid of opiate activity that was administered intraperitoneally or intracerebroventricularly to mice under morphine analgesia were investigated. The interaction of this peptide with the analgesic effects of morphine was examined using the hot plate and the tail flick test.
• 2.2. Intraperitoneal acute treatment with DTγE did not change the analgesic effects of morphine.
• 3.3. Intraperitoneal semi-chronic treatment performed for 4 days with DTγE enhanced morphine analgesic effects.
• 4.4. The intracerebroventricular acute treatment with DTγE reduced morphine analgesia in a dose-dependent way.
• 5.5. These results indicate that DTγE, although devoid of opioid activity per se, may interact with the opioid system, probably through an indirect mechanism.

     

Noradrenergic and opioidergic influences on the antinociceptive effect of clomipramine in the formalin test in rats

Although tricyclic antidepressant are especially useful in the treatment of chronic pain conditions, most of the work about its mechanism of action has been made on acute pain tests. The present study was aimed at studying the role played by noradrenergic and opioidergic influences on the antinociceptive activity of subchronically administered clomipramine in the formalin test (a tonic pain model) in rats. Clomipramine produced antinociception after 7 days, administration (2.5 mg/kg/day), an effect equivalent to that obtained by acute morphine (5 mg/kg). The antinociceptive effect of clomipramine was inhibited by the following: nonspecific blocking of alpha₁-and alpha₂-adrenoceptors by phentolamine, specific blocking of alpha₁-adrenoceptors by prazosin; stimulation of alpha₂ receptors by clonidine; and blocking of the opioid receptors by naloxone. Blocking the alpha₂-receptors with yohimbine did not antagonize the effect of clomipramine. These results suggest that clomipramine produces antinociception in this test, partly via the participation of the endogenous opioid system and partly by further activating or potentiating previously activated noradrenergic pathways which are involved in the control of pain information.     

Involvement of kappa opioid receptors in formalin-induced inhibition of analgesic tolerance to morphine in mice

This study examined the role of kappa opioid receptors (KOR) in the mechanism underlying tolerance to the analgesic effects of morphine induced by chronic pain. The analgesic effect of morphine (10 mg kg(-1)), estimated by the tail-flick test in mice, gradually decreased during repeated daily morphine treatment. A significant decrease in the analgesic effect of morphine was seen on the fifth day of repeated morphine treatment compared with the first day. Chronic pain was induced by subcutaneous administration of 2% formalin into the dorsal part of the left hind paw, which significantly inhibited development of tolerance to morphine analgesia. The effect of formalin-induced pain on inhibition of morphine tolerance was reversed by the KOR antagonist nor-binaltorphimine. Furthermore, an antisense oligodeoxynucleotide, but not a missense oligodeoxynucleotide, against KOR completely suppressed the inhibitory effect of formalin-induced pain on morphine tolerance. Naltrindole, an antagonist of delta opioid receptor, did not affect chronic-pain-induced tolerance to morphine. Our findings show that the inhibitory effect of chronic pain on analgesic tolerance to morphine is mediated by KOR rather than delta opioid receptors.     

Stress and morphine analgesia: alterations following p-chlorophenylalanine

Recent studies have shown that while the analgesic responses induced by certain stressors appear to be related to morphine analgesia, the analgesic responses to other stressors do not. Para-chlorophenylalanine (PCPA), a potent tryptophan-hydroxylase inhibitor has been shown to decrease both basal pain thresholds and morphine analgesia on the flinch-jump test. To assess further the relationship between morphine and stress-induced analgesia, PCPA's effect upon the analgesic responses to cold-water swims, 2-deoxy-D-glucose, inescapable foot shock and morphine were determined using the flinch-jump and tail-flick tests. PCPA, which produced an 85% depletion of brain serotonin, significantly decreased jump thresholds while significantly increasing tail-flick latencies. Similarly, while morphine analgesia was decreased by PCPA on the flinch-jump test, it was not affected on the tail-flick test. The analgesic jump thresholds induced by cold-water swims and 2-deoxy-D-glucose as well as the increase tail-flick latencies induced by foot shock were unaffected by PCPA. These results are discussed in terms of PCPA's differential effects upon basal nociception and morphine analgesia and in terms of further dissociation between morphine and stress-induced analgesia.     

Modification of morphine analgesia by venlafaxine in diabetic neuropathic pain model

BackgroundThe purpose of this study was to investigate the influence of single or chronic (21 days) administration of the serotonin and noradrenaline reuptake inhibitor, venlafaxine, on the antinociceptive action of the opioid receptor agonist, morphine, in streptozotocin (STZ)-induced hyperalgesia.MethodsThe studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli. Diabetes was induced by a single administration of STZ (40 mg/kg, im).ResultsVenlafaxine was shown to modulate analgesic activity of morphine in STZ-induced hyperalgesia. However, whereas acute co-administration of venlafaxine increased the analgesic activity of morphine, chronic treatment with venlafaxine attenuated opioid efficacy.ConclusionDepending on the mode of administration (single or long-term), venlafaxine modulates analgesic activity of morphine. Further investigations are necessary to clarify the mechanisms of these interactions, which may be clinically relevant.     

Central monoaminergic mechanisms in mice and analgesic activity of spiradoline mesylate, a selective kappa-opioid receptor agonist.

We assessed the roles of brain monoaminergic systems in the analgesic action of spiradoline, a novel kappa-opioid agonist, behaviorally and biochemically by using noradrenaline (NE) and serotonin (5-HT) uptake inhibitors. Analgesic activity was evaluated by measuring latency time in the mouse tail-pinch test. Spiradoline at intramuscular doses of 0.3 mg/kg or more elicited a significant analgesic effect and the metabolism of both NE and 5-HT was significantly increased in brainstem and cortex. Pretreatment of the mice with imipramine, desipramine or clomipramine caused marked potentiation of spiradoline analgesia, whereas reserpine and phenoxybenzamine inhibited it. Morphine analgesia was enhanced by clomipramine but not by imipramine, desipramine or phenoxybenzamine. These results suggest that excitation of noradrenergic and serotonergic pathways in the brain appears to be involved in spiradoline analgesia, and that, as regards tail-pinch nociception, the kappa-opioid agonist acts on the noradrenergic pathway more potently than morphine.     

Efficacy of administration of dexfenfluramine and phentermine, alone and in combination, on ingestive behavior and body weight in rats

 Cocaine, which non-selectively blocks the reuptake of the monoamines serotonin, dopamine and norepinephrine, produces weak antinociceptive effects and increases the antinociceptive effects of low- to intermediate-efficacy mu opioid agonists in rhesus monkeys. In the present study, the antinociceptive effects of more selective monoamine reuptake inhibitors administered alone and in combination with mu opioid agonists were evaluated in rhesus monkeys using a warm-water tail-withdrawal assay of thermal nociception. Like cocaine, the selective serotonin reuptake inhibitors clomipramine (0.01–3.2 mg/kg) and fluoxetine (0.1–10 mg/kg) produced weak antinociceptive effects. Pretreatment with the serotonin receptor antagonist mianserin (0.032–0.32 mg/kg) produced rightward and downward shifts in the clomipramine dose-effect curve, suggesting that the effects of clomipramine were mediated by serotonin receptors. Combination of clomipramine with the low efficacy mu agonist nalbuphine or the intermediate efficacy mu agonist morphine produced more antinociception than did the mu agonists alone. Fluoxetine also produced a small leftward shift in the morphine dose-effect curve. The selective norepinephrine reuptake inhibitors nisoxetine (0.1–10 mg/kg) and tomoxetine (0.1–10 mg/kg) and the selective dopamine reuptake inhibitors bupropion (0.032–3.2 mg/kg) and GBR 12909 (0.1–10 mg/kg) did not produce antinociception or increase antinociception induced by nalbuphine or morphine. In fact, GBR 12909 produced dose-dependent allodynia and reduced the maximal antinociceptive effects of morphine. These results suggest that inhibition of serotonin reuptake is sufficient to produce weak antinociceptive effects and enhance the antinociceptive effects of low efficacy mu opioid agonists. These results also suggest that the effects of cocaine on serotonin reuptake may contribute to cocaine’s antinociceptive effects in rhesus monkeys. Received: 5 May 1997 / Final version: 30 July 1997     

Morphine analgesia after intrathecal administration of a narcotic agonist, chloroxymorphamine and antagonist, chlornaltrexamine

The spinal effects of two opiate compounds with nonequilibrium properties, chloroxymorphamine (COA) and chlornaltrexamine (CNA), were studied in the rat. Permanent indwelling cannulas to the spinal subarachnoid space allowed repeated injections of drugs to be made into a circumscribed receptor population. At various times after injection of the alkylating agents, the analgesic efficacy of morphine was measured. A single intrathecal injection of the antagonist, CNA, was found to dramatically inhibit the analgesic effect of intrathecally administered morphine challenges from 2 to 13 days. Pretreatment with CNA also reduced the analgesic effect of subcutaneously administered morphine, but only mildly compared to the potent inhibition of intrathecally administered morphine. In contrast to CNA, pretreatment with naltrexone intrathecally did not significantly inhibit the analgesic effect of intrathecal morphine challenges. Unlike the pure antagonistic effect of CNA, a single intrathecal injection of COA produced an immediate dose-related analgesia. Subsequently, the analgesic effect was absent, and replaced by a potent and long-term antagonism of morphine analgesia, which was still present as long as 21 days after COA. As was found with CNA, the inhibition by COA of the analgesic effect of morphine administered intrathecally was much more potent than that of subcutaneously administered morphine. The intrathecal injection of chlorambucil, a non-specific alkylating agent, produced no analgesia and did not affect the analgesic efficacy of subsequent treatment with morphine. The non-opioid analgesic effect of serotonin injected intrathecally was not affected by pretreatment with COA, and only slightly inhibited by the previous spinal injection of CNA. Using this test system, our results indicate that COA and CNA possess a much greater potency and longer duration of inhibition of narcotic receptors than previously demonstrated.