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Home , Cinnarizine, Verapamil

Indian J PhysioJ Pharmacol 1993; 37(3): 238-240

MODIFICATION OF TRICYCLIC ANALGESIA BY BLOCKERS

ABHAY V. MUTRAL AND CHANDRABHAN T. CHOPDE*

Department ofPharmaceutical Sciences, Nagpur University Campus, Nagpur - 440 010

( Received on Fcbrurary 27, 1992)

Abstract: The influence of calcium channel blockers (CCI3) on the analgesic activity of tricyclic antidcpressants (TCA) was examined using hot plate (thermal) and writhing (chcmical) method. Intraperitoneal injections of TCA, and or CCB viz: , , and per se produced analgesia. The Analgesic effect of TCA was further enhanced by prior treatment with CCI3. The increase in TCA analgesia could not be ascribed to unitary mechanism but could possibly bc mediated by and/or nonopioid systems. These results clcarly provide an evidcnce that a combination treatment of CCB and TCA may permit reduction of the TCA doses while treating chronic pain of organic origin.

Key words: calcium channel blockers tricylic anal5esia

INTRODUCTION analgesia was calculated (8) and the mean percent analgesia was computed for a representative group. There is now substantial evidence to indicate that tricyclic antidepressants (TCA) produce analgesia . Test latency - Control latency % AnalgeSIa == x 100 (l,2) and are used to alleviate chronic pain (13), but 60 - Control latency their precise mechanism appears to be quite complex and unclear. Similarly, calcium has an important The writhing syndrome was elicited by physiological in the control of pain either through direct administration of acetic acid (10 mg/kg, 1%, LP) and action or through modulation of endogenous substances the number of writhes displayed from 5 min to 15 min (4,5) and calcium channel blockers (CCB) have been were recorded. Analgesia was represenlCd by percentage reproted to produce analgesic effects in mice (6). TCA inhibition of writhes and was calculated according to used clinically in chronic pain leads to severe side the formula, % inhibitor of writhes == S-TIS x 100. effects. So an attempt to investigate the cambined Where S is the number of writhes in control and T is analgesic effect of CCB and TCA in mice has been the number of writhes in drug treated animals (6). made. Drugs: Imipramine hydrochloride (IMA) and METHODS amitriptyline hydrochloride (AMT) (Torrent Labs) cinnarizme, nifedipine, verapamil and nicardipine Male NIH mice weighing 20-25 gm maintained (Sigma Chemical Co., U.S.A.). Cinnarizine and under 12 hour light dark cycle were used. Two analgesic nifedipine were suspended in 5% gum acacia, whereas tests were used: the hot plate test and writhing test. In all other drugs solutions were prepared in 0.9% NaC!. hot plate test, the surfacre temperature was maintained All the drugs were administered intraperitoneally in a at 50±I°C (7) throughout the experiment. Animals volume of 0.1 ml per mouse. showing reaction time between 10-15 sec for licking of hind paw and or jumping (whichever occured first) Treatment protocol: The various TCA and CCB were used for experiments and a cut off time of 60 sec were administered individually and in combination at was used to avoid tissue injury (7) and the pcrcent the dose of 20 mg/kg respectively in hot plate method.

*Corrcsponding Author Indian J Physiol Pharmacol 1993; 37(3) TCA Analgesia and Calcium Channel Blockers 239

For writhing test only IMA (10 mgjkg) was used TABLE II: Analgesic effect of Calcium channel blockers individually and in combination with verapamil 5 mg/ and TCA as assayed by acetic acid writhing test. kg and nicardipine 10 mg/kg. In both the tests, CCB Treatment dosemg/kg n % Inhibition ofwrithes were given 30 min prior to TCA administration and (Mean±SD) the response was noted at next 30 min. Statistical Vehicle 8 analysis of the results was done by upaired test and Imipramine 10 8 60.5±3.02* P<0.05 was considered statistically significant. Verapamil 5 10 27.4±1.88*

a RESULTS AND DISCUSSION V~arnil 5 8 85.36±2.28 Imipramine 10 Tricyclic antidepressants and calcium channel Vehicle 7 blockers if given individually produced singificant Nicardipine 10 9 26.68±1.6* analgesia in both the tests. However, when given Nicardipine 10 7 82.07±1.8a + together, the analgesic effect was greater than either of Imipramine 10 them given alone (Table I and II). In hot plate test Significant at P< 0.001 when compared with (*) vehicle control and IMA analgesia was increased from 15.5% to 26.22%, (a) imipramine alone respectively. while in writhing method % inhibition of writhes was raised from 60.5% to 85.36% by verapamil and TCA analgesia are not fully clear. The analgesic a~tion nicardipine. The mechanism by which CCB increase of TCA is linked to their direct activity on the structure of (CNS) mediating pain TABLE I: Analgesic effect of Calcium Channel blockers perception, independent of their effects on mood and and antidepressants as assayed by hot plate test. by blocking of alpha-2 adrenoceptors and or amine re­ Treatment n % Analgesia uptake (9). The CCB also inhibit alpha-2 adrenoceptors 20 mg/kg, i.p.) (Mean±SD) at nor-adrenergic axon terminals in CNS (10,11). It Vehicle 5 has been reported that the analgesic properties of Imipramine 5 15.45±O.3* antidepresants might be mediated by an interaction with Amitriptyline 6 15.03±1.69* opiate receptors in brain (12). Similarly a close relation Vehicle 5 ship between CCB and Il opiate receptors has been Verapamil 6 14.85±O.47* demonstrated (13). Verapamil+Amitriptyline 6 27.46±0.98a Verapamil+Imipramine A 6 26.0I±I.98 The increase of TCA analgesia could also be Vehicle 5 ascribed to their calcium channel blocking activity or Nifedipine 5 12.41±O.95* Nifedipine+Amitriptyline 5 29.08±1.56a altered calcium disposition, and because this effect is Nifedipine±lmipramine 6 20.84±1.3IA shared by all CCB, EDTA, EGTA and lanthanum which Vehicle 5 by decreasing calcium cellular avialability show Nicardipine 5 15.90±1.27* antinociceptive activity (14, 15). The intracerebroven­ Nicardipine+Amitriptyline 5 25.76±1.88a tricular injection of calcium is reported to produce Nicardipine+Imipramine 6 26.22±1.Q9A hyperalgesia (4). The exact mechanism responsible for Vehicle 5 the additive analgesic effect of TCA and CCB remains Cinnarizine 6 9. 18±O.79* to be elucidated. Cinnarizine+ Amitriptyline 6 33.82±0.47a Cinnarizine+Imipramine A 5 23.42±1.33 ACKNOWLEDGEMENTS Signifie,ant at P < 0.001 when compared with (*) vehicle treated control, (a) amitriptyline alone and (A) imipramine alone respectively. The authors thank UGC New Delhi, for the The results shown are for 20 mg/kg, i.p. of TCA and CCB. financial support. 240 Muthal and Chopde Indian J Physiol Pharmacol 1993; 37(3)

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