Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 38, Num. 3, 2006, pp. 181-184

Indian Journal of Pharmacology, Vol. 38, No. 3, May-June, 2006, pp. 181-184

Research Paper

Analgesic activity of venlafaxine and its interactions with tramadol, celecoxib and amlodipine in mice

Jha PK, Mazumdar B, Bhatt JD

Department of Pharmacology, P D U Medical College, Rajkot
Correspondence Address:Department of Pharmacology, P D U Medical College, Rajkot, jhapankajku@yahoo.co.in

Code Number: ph06044

Abstract

Keywords: Antidepressant, tail flick latency, writhing

Introduction

Chronic pain is often accompanied by depression.[1] Selective serotonin reuptake inhibitors (SSRI) used in the management of depression, by increasing the serotonin level, inhibit the release of transmitters carrying the pain sensation from nerve endings.[2] There is ample evidence to suggest that descending pain inhibitory pathways involve monoamines such as noradrenaline (NA) and 5-hydroxytryptamine (5-HT, serotonin). Spinal inhibition of pain, brought about by inhibiting NA and 5-HT reuptake, is one of the major mechanisms of action of opioid analgesics.[3] The release of transmitters, carrying the pain sensation from nerve endings, is regulated by intracellular calcium level, which also regulates the synthesis of prostaglandins.[4] In the absence of any report of analgesic activity of venlafaxine in animals, the present study was planned to investigate whether:

a. It has any analgesic activity?
b. And if so, how does it interact with opioid analgesic tramadol, COX-2 inhibitor celecoxib and calcium channel blocker amlodipine?

Materials and Methods

The study was carried out on albino mice of either sex (20-30 g), maintained under standard laboratory conditions. Venlafaxine (Sun Pharmaceuticals, Baroda, India), amlodipine (Sarabhai Chemicals, Baroda), tramadol (Sarabhai Chemicals, Baroda) and celecoxib (Intas Pharmaceuticals, Ahmedabad), were dissolved in distilled water (DW), dimethyl sulfoxide (DMSO), isotonic saline (NS) and methyl alcohol (MA), respectively. All the drugs and vehicles were administered in a total volume of 0.1 ml, intraperitoneally (i.p.).

The animals were divided into control (saline, administered 15 min prior to the test), vehicle treated (DW, NS or MA were administered 15 min before, whereas DMSO was given 6.25 h prior to the test) and drug treated groups, of 6 animals each. The drugs under investigation were administered 15 min prior to their individual group tests. However, amlodipine treatment was given 6.25 h prior to the test.

Determination of analgesic activity
Two different tests were employed to study the analgesic activity.

1. Tail flick test: Analgesic activity was measured by the tail flick method, using the analgesiometer as described by D'Armour and Smith.[5] For each animal, the tail flick latency was obtained thrice before drug administration and mean was used as pre-drug latency. The tail flick latencies were measured at 0, 0.25, 0.5, 1, 1.5, 2 and 3 h after administration of vehicle or drug(s). For animals that did not respond within the cut-off time of 10 seconds, the value of the cut-off time was considered as latency period for that animal.[6]

2. Writhing test: Writhing was induced in mice by intraperitoneal administration of 0.1 ml of 1% acetic acid. The number of writhing movements was counted for 20 minutes. The writhing test was performed after the administration of the vehicle or drug.

Statistical analysis
Group results are expressed as mean±SEM. One-way ANOVA followed by either Dunnett's or Tukey-Kramer, post hoc tests of significance was applied for multiple comparisons amongst different groups. P < 0.05 was regarded as statistically significant.

Results

Analgesic activity of individual drugs

(a) Venlafaxine
Venlafaxine in doses of 5 and 7.5 mg/kg did not have any effect on tail flick latency. However, doses of 10 and 22.5 mg/kg, produced dose dependent antinociceptive effect. The antinociceptive effect started at 0.5 h, reached peak at 1 hour and persisted for 2 h and it disappeared at the end of 3 h. [Table - 1]

Venlafaxine in the dose of 10.0 mg/kg produced significant decrease in the number of writhes suggesting its antinociceptive effect. The lower doses of venlafaxine (5.0 and 7.5 mg/kg) failed to produce any decrease in the number of writhes. [Table - 3]A

(b) Tramadol
Tramadol, at 10 mg/kg did not have any antinociceptive effect when tested by tail flick test. The antinociceptive effect was noted with 22.8 mg/kg with onset at 1.0 h, peak at 1.5 h and it persisted throughout the 3 h of study. [Table - 1]

Tramadol in the doses of 5.0 mg/kg and 10.0 mg/kg produced a marked decrease in the number of writhes as observed over a test period of 20 min, which suggests a strong antinociceptive effect. However, 2.5 mg/kg dose of tramadol did not produce any significant effect. [Table - 3]A

(c) Celecoxib
In the tail flick test, antinociceptive effect of celecoxib was observed only at a dose of 30 mg/kg, with latency of 1 h. Peak effect was seen at 2 h and it persisted for entire duration of 3 h. Lower dose (15 mg/kg) of celecoxib did not produce any change in the latency period. [Table - 1]

Celecoxib in the dose of 15.0 mg/kg, produced significant decrease in the number of writhes. Celecoxib 7.5 mg/kg failed to produce any effect. [Table - 3]A

(d) Amlodipine
In tail flick test, with a dose of 3.5 mg/kg of amlodipine, significant antinociceptive effect was observed 6.25 h after the treatment, reaching peak at 7.0 h after amlodipine administration and the effect significantly persisted for the entire test period. [Table - 1]

Significant antinociceptive effect was however observed with amlodipine at a lower dose (3 mg/kg) in the writhing test. [Table - 3]A

Drug combinations
Sub-analgesic dose of venlafaxine (7.5 mg/kg) was combined with sub-analgesic doses of tramadol (10 and 2.5 mg/kg), celecoxib (15 and 7.5 mg/kg) and amlodipine (3.0 and 2.5 mg/kg) for tail flick test and writhing test respectively.

Venlafaxine in combination with tramadol produced a significant increase in tail flick latency as compared to control or either of the treatment alone. [Table - 2]

The combination also decreased number of writhes as compared to control value or either of the treatment alone. [Table - 2]B

Similarly venlafaxine in combination with amlodipine was also found to have significant antinociceptive action in both the tests when they were combined in the sub-analgesic doses as compared to control value or either of the treatment alone. [Table - 2] and [Table - 3]B

In tail flick latency test, combination of the sub-analgesic doses of celecoxib and venlafaxine failed to achieve significant antinociceptive effect throughout the study, except at 1.5 and 2.00 h when they marginally increased the duration of tail flick latency. [Table - 2]

However the combination produced significant decrease in number of writhes as compared to control or either of the treatment alone. [Table - 3]B

Discussion

Pain is an unpleasant sensation, with a large subjective component. It is often accompanied by depression and a feeling of hopelessness.[1]

Several antidepressants are known to possess intrinsic analgesic acitivity.[7],[8] Venlafaxine, a widely used newer generation antidepressant, has been cited as a promising drug for neuropathic pain control.[9],[10] We also found venlafaxine to have an analgesic effect in both the tail flick and the writhing tests. There is ample evidence to suggest the involvement of monoamines such as NA and 5-HT in descending pain pathways.[11] Antidepressants such as venlafaxine mainly block reuptake of the above neurotransmitters. This could be the mechanism of its analgesic action. However, the possibility of other mechanisms cannot be ruled out. Extensive research, over the past two decades, has revealed the pivotal roles of serotonergic and noradrenergic neurotransmitter systems in nociception and analgesic action of opioids.[12],[13] In addition, there is sufficient data to suggest that opioid pathways may play a significant role in the mechanism of action of antidepressant drugs.[14] Studies have shown that tramadol activates monoaminergic spinal inhibition of pain by inhibiting noradrenaline and serotonin uptake and, to a lesser extent, dopamine uptake.[3],[13] Antinociception produced by SSRIs has been shown to be blocked by naloxone.[1],[8]

Venlafaxine bears a close structural similarity to tramadol and thus shares a number of its molecular and pharmacological features.[9],[15] In confirmation of these, our findings suggest that if an opioid analgesic is combined with an SSRI, analgesia can be achieved at sub-analgesic doses of each.

L and N types of Ca ²⁺ channels, particularly the latter, are important in controlling the release of neurotransmitters from peripheral and central terminals.[16] Blockers of N-type Ca ²⁺ channels can prevent nociceptive signaling.[17] In order to see the interaction between venlafaxine and amlodipine, a combination of sub-analgesic doses of both were used. This produced a significant increase in the tail flick latency and decrease in the number of writhing movements, implying an additive effect.

There have been no reports so far about the use of COX-2 inhibitors along with SSRIs for pain relief. Since our study has demonstrated the analgesic potential of venlafaxine, we ventured to study a possible interaction. Sub-analgesic doses of venlafaxine and celecoxib, when combined, produced a significant antinociceptive effect in the writhing test. However, the results were not convincing in the tail flick test.

From this study, we conclude that venlafaxine, a selective serotonin reuptake blocker, can produce dose dependent antinociceptive action per se and additive antinociceptive effect when combined with tramadol, amlodipine and celecoxib. Observations from these animal studies need to be tested in clinical trials.

Acknowledgments

References

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