zimeldine and Pain

Zimelidine inhibits the central neuronal reuptake of serotonin and has undergone clinical evaluation as an antidepressant. Twenty patients with chronic pain of non-malignant origin (mean duration 15.8 years) were entered into a double blind cross-over study of the analgesic efficacy of zimelidine and placebo. The duration of each treatment phase was 6 weeks and there was a comprehensive assessment of each patient prior to the commencement and at the completion of the study, during a brief period of hospitalisation. Zimelidine was superior (P less than 0.05) to placebo with respect to pain relief based on a global assessment (by the clinical investigators) performed at the completion of each treatment phase. However, there was no significant difference in analgesic efficacy between the zimelidine and placebo treatment phases based on the following criteria: (a) changes in the minimum effective blood concentration of pethidine necessary to provide pain relief in each patient, measured during a pethidine infusion of 1.67 mg/min for 60 min; (b) changes in pain scores estimated by patients using the visual analogue pain scale (VAPS); (c) changes in patients' estimates of pain intensity associated with various daily activities. Significant pain relief was apparent within 2-3 days in those patients who had a beneficial effect, which contrasts with the documented 3-4 weeks for maximal antidepressant effects. The results of this study suggest that serotonin reuptake blockers do not provide consistent pain relief in patients with chronic pain, but may contribute an analgesic effect in the treatment of some patients.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pain; Personality Tests; Psychophysiologic Disorders; Random Allocation; Sick Role; Zimeldine

Spinally administered mu opioid agonists produce potent antinociception and inhibition of gastrointestinal transit. Blockade of 5-hydroxytryptamine (5-HT) or norepinephrine (NE) uptake potentiates intrathecal (i.t.) DAMGO antinociception. To determine whether 5-HT and NE uptake blockade will also potentiate the gastrointestinal inhibition, mice were treated with zimelidine, desipramine or saline, followed by i.t. DAMGO and tested for tailflick antinociception or inhibition of gastrointestinal transit. DAMGO produced antinociception dose-dependently (ED50 = 4.6 ng). Zimelidine (10 mg/kg, s.c., 1 hr before DAMGO) produced a 6.2-fold leftward shift in the antinociceptive dose-response curve (ED50 = 0.73 ng). Desipramine produced a 5.3-fold shift (ED50 = 1.4 ng). DAMGO also produced a dose-dependent inhibition of gastrointestinal transit (ED50 = 117 ng). However, zimelidine or desipramine treatment did not affect DAMGO inhibition of gastrointestinal transit (ED50 = 80 ng.).

Topics: Animals; Desipramine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Gastrointestinal Motility; Injections, Spinal; Male; Mice; Norepinephrine; Pain; Receptors, Opioid, mu; Serotonin; Zimeldine

The behavioural response to intrathecal serotonin (5-HT) was examined in mice after acute and after withdrawal of repeated treatment with the 5-HT uptake inhibitor zimelidine or the 5-HT receptor antagonist metergoline. Intrathecal 5-HT elicits a response consisting of biting or licking of the lower part of abdomen and reciprocal hindlimb scratching, indicative of nociceptive stimulation. Acute injection of zimelidine (20 mg/kg) significantly increased the response to intrathecal 5-HT (0.25-1 micrograms) whereas a single dose of metergoline (5 mg/kg) completely blocked the response to intrathecal 5-HT (2 micrograms). The behavioural response to intrathecal 5-HT (0.25-2 micrograms) was not significantly changed 48 hr after withdrawal of repeated treatment with zimelidine (2 x 10 mg/kg/day for 14 days) or metergoline (2 x 2.5 mg/kg/day for 14 days). In the present experiments acute zimelidine appeared to increase nociceptive responsiveness, whereas metergoline had the opposite effect. This study does not provide evidence that long-term treatment with zimelidine or metergoline leads to adaptive changes in the response to spinal cord 5-HT receptor stimulation.

Topics: Animals; Injections, Intraperitoneal; Injections, Spinal; Male; Metergoline; Mice; Nociceptors; Pain; Receptors, Serotonin; Serotonin; Zimeldine

Tricyclic antidepressants have shown antinociceptive properties in some, but not in all, animal studies using the tail flick test. Tail flick latency has been found to be strongly negatively correlated to tail skin temperature with its highest correlation found when the temperature is measured close to the heated spot. The selective 5-HT reuptake inhibitor zimelidine, as well as the noradrenaline reuptake inhibitor desipramine, increased tail flick latencies. However, this increase could largely be explained by a concomitant reduction in tail skin temperature. The highest dose of desipramine investigated (25 mg/kg) seemed to possess antinociceptive properties in this test also after correction for the fall in tail skin temperature. Lower doses of desipramine (5 and 15 mg/kg) and zimelidine (5, 20 and 30 mg/kg) were either inactive or their effect on tail flick latency could be explained by the fall in tail skin temperature. The apparent antinociceptive effect of zimelidine in the tail flick test thus seems to be due to an effect on tail skin temperature. Desipramine also seems to have its main effect due to a similar mechanism; however, the highest dose of desipramine used induced significant antinociception.

Topics: Analgesics; Animals; Body Temperature Regulation; Desipramine; Hot Temperature; Male; Pain; Rats; Rats, Inbred Strains; Zimeldine

The behavioural response to intrathecal substance P (SP) was evaluated following acute and chronic administration of the selective serotonin reuptake inhibitor zimelidine. A single dose of zimelidine (10 mg/kg) attenuated the response to SP by approximately 40%, in agreement with previous findings that acute administration of zimelidine reduces nociceptive behaviour. Twenty-four hours following the withdrawal of long-term treatment with zimelidine (10 mg/kg X 2 daily for 14 days) the behavioural response to SP was increased by 116%. This may indicate the development of supersensitivity to SP, or may reflect an increased responsiveness to noxious stimuli due to reduced serotonergic inhibition.

Topics: Animals; Behavior, Animal; Drug Interactions; Injections, Spinal; Mice; Pain; Pain Measurement; Substance P; Zimeldine

The selective inhibitor of the reuptake of 5-hydroxytryptamine (5-HT), zimelidine, was administered intraperitoneally to mice (10 mg/kg) and nociceptive sensitivity was evaluated using the formalin test (20 microliters of 1% formalin, injected subcutaneously) and the assay for substance P (5 ng administered intrathecally). Zimelidine increased the behavioural response to formalin, but reduced the response to substance P. These effects of zimelidine seemed to be unchanged after chronic treatment (2 X 10 mg/kg for 14 days). It is suggested that zimelidine produces a central antinociceptive effect, but elicits a peripheral hyperalgesia, which predominates in the formalin test.

Topics: Animals; Behavior, Animal; Formaldehyde; Male; Mice; Pain; Substance P; Zimeldine

The effect of direct intrathecal injection of p-chloroamphetamine (PCA) into the lumbar subarachnoid space was investigated in mice. PCA (0.6 - 20 micrograms) induced a dose-related prolongation of response latencies in the tail-flick test, but failed to affect the hind-paw lick response in a hot-plate test employing slowly rising temperature. PCA (5 micrograms) given intracerebroventricularly did, however, significantly elevate the response temperature in the hot-plate test. The antinociceptive effect of PCA in the tail-flick test was prevented by spinalization, by pretreatment with the selective serotonergic re-uptake blocker zimelidine (20 mg X kg-1 i.p.) and by the serotonin synthesis inhibitor p-chlorophenylalanine (300 + 300 + 150 mg X kg-1 i.p. 72, 48 and 24 h before test). It is concluded that PCA given intrathecally releases serotonin from spinal terminals, which may under certain conditions induce antinociception.

Topics: Amphetamines; Animals; Dose-Response Relationship, Drug; Injections, Spinal; Male; Mice; Mice, Inbred Strains; p-Chloroamphetamine; Pain; Reaction Time; Receptors, Serotonin; Serotonin; Spinal Cord; Zimeldine

Thresholds to noxious heat stimulation were increased following microinjection of zimelidine, an inhibitor of 5-hydroxytryptamine (5-HT) re-uptake, into the nucleus raphe magnus (NRM) of rats. Pretreatment with intraperitoneally given cinanserin reduced this effect but pretreatment with intraperitoneally given phenoxybenzamine did not. Fenfluramine, which causes the release of 5-HT from synaptic terminals also elevated nociceptive thresholds following microinjection into NRM. Subanalgesic doses of morphine or zimelidine elevated nociceptive thresholds when microinjected together into NRM. The elevation of nociceptive threshold produced by microinjection of morphine into NRM was reduced by simultaneous microinjection of cinanserin into NRM. Cinanserin alone had no effect when microinjected into NRM. These findings suggest that inhibition of the re-uptake of 5-HT in NRM can elevate nociceptive thresholds and that there may be an interaction between the effects of morphine and 5-HT in NRM.

Topics: Animals; Brain Stem; Cinanserin; Hot Temperature; Male; Morphine; Pain; Phenoxybenzamine; Raphe Nuclei; Rats; Rats, Inbred Strains; Sensory Thresholds; Serotonin; Zimeldine

The authors report a case involving a 65-year-old woman with DSM-III criteria for major unipolar depression in whom the administration of zimelidine, a potent and selective 5-hydroxytryptamine reuptake inhibitor, led to the development of a hypersensitivity reaction characterized by a severe headache, low grade fever, abnormal liver enzymes, and generalized myalgia 10 days after initiation of treatment. The most novel aspect of this hypersensitivity reaction to zimelidine was the development of abnormalities in muscle creatine phosphokinase in conjunction with the myalgia.

Topics: Aged; Creatine Kinase; Depression; Female; Humans; Liver; Muscles; Muscular Diseases; Pain; Zimeldine

Topics: Adult; Antidepressive Agents; Brompheniramine; Female; Headache; Humans; Liver; Muscles; Pain; Pyridines; Zimeldine

The effects of the specific 5-HT uptake inhibitors alaproclate and zimelidine, the 5-HT releasing compound p-chloroamphetamine (PCA) and the specific NA uptake inhibitor desipramine on pain sensitivity were examined in male rats using the hot-plate and tail-flick methods. The effects of alaproclate and zimelidine on 5-HT uptake mechanisms in the hypothalamus and spinal cord were also studied. Alaproclate, zimelidine, PCA and desipramine produced hypoalgesia in the hot-plate but not in the tail-flick test. Naloxone (1 mg/kg) failed to block the hypoalgesia produced by alaproclate and PCA in the hot-plate test. Zimelidine but not desipramine pretreatment blocked the analgetic action of PCA in the hot-plate test. Alaproclate significantly enhanced morphine analgesia in the hot-plate test but did not affect morphine analgesia in the tail-flick test. In contrast, zimelidine tended to enhance and significantly prolonged morphine analgesia in the tail-flick test but did not affect morphine analgesia in the hot-plate test. Zimelidine inhibited 5-HT uptake with equal potency in the hypothalamus and spinal cord, while alaproclate produced a greater inhibition of 5-HT uptake in the hypothalamus. These findings show test-specific effects after enhancement of central 5-HT neurotransmission. It is suggested that various aspects of pain sensitivity and morphine analgesia may involve different 5-HT pathways in the brain and spinal cord. Moreover, 5-HT pathways in the forebrain may mediate analgesia of a non-opiate type.

Topics: Alanine; Analgesia; Animals; Behavior, Animal; Brompheniramine; Desipramine; Dose-Response Relationship, Drug; Male; Morphine; Naloxone; p-Chloroamphetamine; Pain; Pyridines; Rats; Serotonin; Zimeldine

1 The effect of selective inhibition of 5-hydroxytryptamine (5-HT) re-uptake by fluoxetine and zimelidine on morphine- and pethidine-induced antinociception was studied in rats. The hot plate (55 degrees C) and tail flick test procedures for measurement of analgesia were employed to assess antinociception. 2 Pretreatment with fluoxetine and zimelidine potentiated the antinociceptive effect of morphine (4.5 mg/kg, as base); zimelidine was without effect on a lesser dose of morphine (3.0 mg/kg, as base). 3 Pretreatment with zimelidine but not fluoxetine, significantly attenuated pethidine-induced antinociception (24 mg/kg, as base) and prevented the expression of pethidine-induced antinociception at a lesser 10 mg/kg (as base) dose of pethidine. 4 These and other results support (a) a role for 5-HT in the expression of morphine-induced antinociception, and (b) a different mode of antinociceptive action of morphine and pethidine. The role of 5-HT in pethidine-induced antinociception remains unclear.

Topics: Animals; Brompheniramine; Drug Interactions; Male; Meperidine; Morphine; Pain; Pyridines; Rats; Reaction Time; Serotonin Antagonists; Zimeldine