Involvement of Dopamine D2 and 5-HT IA Receptors in Roxindole-Induced Antinociception
Indi an Journal of Experiment al Biology Vol. 37, March 1999, pp. 23 4-237
Involvement of dopamine D2 and 5-HT IA receptors in roxindole-induced antinociception
Ipe Ninan & S K Kulkarni* Ph armaco logy Di vision, Universit y In stitute of Pharmaceutical Sciences, Panj ab Uni versity, Chand igarh )60014, Indi a Received 23 March 1998; revi sed 27 November 1998
Rox i Il dole. a DA O2 receptor ago ni st (2-1 6 mglkg) produ ced dose-dependent i ncrease in percent age reserpine (2 mg/kg)-i nduced hyperalgesia. Th is reversal was sensiti ve to blockade by both (-)su lpiri cte (50 mglkg) and (-) pindolol (5 mg/kg). The presen t stud y s~ges t s th at ro xindol e-induced ant inocicepti on is mediated by postsynaptic DA D2 and 5-HTIA rece pt ors.
Rox indole (EMD 49980) is a representati ve of a new severe pain associated with various states of di sease class of dopaminergic drugs, I. e., the indolyl affecting the nervous system, such as. the thalamic butylamines. whi ch lac k structural similarities with syndrome, herpes zoster and Parkinson's either ri gid dopamine (DA ) analogs or ergot di sease' 1.l 2.'J.'4. and a recent study showed that 8-0H deri vatives '. Rox indole ex hibits potent , long lasting DPA T inhibits nociceptive responses by stimulating lS and hi ghl y se le cti ve agoni sti c ac ti ons at presynaptic postsy naptic 5- HT IA recept ors . Dl recept ors with out sti mul atin g pos tsy naptic D2 The present study was undert aken to investi gate the 2 recept ors even at hi gh doses . This selec ti vity makes rol e of D2 and 5-HTI Ar ecept ors in the antinoc iception rox indole a pre-eminent candidate for a novel type of produced by rox indole in nai ve and reserpinised antipsyc hoti c drug wi th out neurological side effects mice. whi ch limit th e usefuln ess of conventi onal D2 Materials and! Methods recept or bl ockers. Within th e past few years, several Allima/s--8 alb/C mi ce (bred in Central Animal new putati ve. selecti ve DA autoreceptor agoni sts House facility of Panj ab Uni versity), weighing 20-25 have been developed, among them are the transfu sed g, were housed under a standard 12 h Iightll2 h dark analog of 3-PPP, (-)-HW 165 , the cycle. The animals were acclimatized to the transdih ydroergo lin e terguri de and the amino laboratory condi tions with free access to food and ergo lin es SDZ 208-9 12 (ref. 3-5). Interest in these water for 24 h before th e ex periment. All experiments putati ve DA Ll ut oreceptor ago ni sts derives largely were undert aken between 09.00 and 13.00 h. from th eir potential use as non-class ical antipsychoti c Technique--The nocicepti ve threshold was drugs. Rox indole, bes id es it s affinit y for Dl receptors, 2 determined as the tail-flick latencies eli cited in has affinity for the 5-HT' A recept or als0 . response to noxI. ous ra dlant' heat·. 16 17 B ase Im' e Consid erable clini cal ev idence suggests th at DA latencies to tail-fl ick withdrawal from th e radi ant heat rece pt or-medi ated mec hani sms may play an important source (3 -4 s) were established. A cut off time of 10 s ro le in modul atin g pa in in humans. A number of was observed to prevent any inj ury to the tail. A animal studies ha ve showed th at DA is involved in minimum of three tria ls, at 2 min intervals, were the regul ati on of noc icepti on. However, th e data recorded for each animal before the test. reported are contradic tory and DA agonis ts have been 6 Antinocicepti on was calcul ated accord ing to the shown to produce either antinocicepti on .7 or 8 y foll owin g fo rmul a: % an tinociceptio ll = 100x(test hyperalgesia . or to have both effects 10. However, latency - basel in e latency) / ( 10 - base li ne latency). some DA agonists have been reported to suppress the Drugs-Roxindo le mesy late (EMD 49980, Merck *Co rres pondent auth or KGaA Biomed Res CNS, Germany), (-) sulp iride NINAN & KULKARNI : DA D2 AND 5-HT1A RECEPTORS IN ROXINDOLE-INDUCED ANllNOCICEPTION 235 hydrochl oride (Research Biochemicals Inc, MA, dissolved in a drop of dilute HCI, volume made up USA), naloxone hydrochloride (Sigma, USA), (-) with di stilled water and pH adequately adjusted. All pindolol (Ranbaxy, India) and reserpine (Loba the drugs were administered intraperitoneally in a Chemicals, India) were used in the study. The drug constant volume of I m1I1oo g of body weight. The solutions were made in di stilled water, except selection of doses was based on previous reports from reserpine and (-) pindolol. Reserpine was dissolved our laboratory. Each group comprised 5-10 mice In a drop of gl acial acetic ac id while pindolol was Reserpine (2 mglkg) was administered 4 h prior
Table I-Reversal of naloxone-induced hyperalgesia by roxindole and its modifi cation by (-) sulpiride and (-) pindolol in mice
No. Treatment (mg/kg) % Antinociception (Mean±SE)
Saline O.ss±oo
2 Naloxone (20) -36.27±4.26
3 Roxindole (4)+Naloxone (20) 2 1.60±1.63'
4 Roxindole (S)+Naloxone (20) S.04±O.S7"
S Sul piride (SO)+Roxindole (4)+Naloxone (20) 0. 16±O. lOh
6 Sulpiride (SO)+Roxindole (S)+Naloxone (20) - S.6S±O.3S C
7 Pindolol (S)+Roxindole (4)+Naloxone (20) -9. IS±O.42h
S Pindolol (S)+Roxindole (S)+Naloxone (20) - 10.4±O.06C
"P 90 80 ::E -w en 70 +f c: CU 60 Q) ::E c: 50 0 ;; Q. Q) 40 .2 u 30 c:0 ;; a c: 20 a « b C 0~ d 10 b 0 2 4 8 16 2 4 8 16 2 4 8 16 Saline Sulpiride (50) Pindolol (5) Fi g. I-Anti nociceptive effect of roxindole (2- 16 mg/kg) and its modification by (-) sulpiride (SO mg/kg) and (-) pindolol (5 mg/kg) in mi ce. a. h .c. ~ P Tab le 2-Reversal of reserpine (4 h post)-induced hyperalgt:sia by Reserpine (2 mglkg, 4 hr prior) pre-treatment roxi ndole and its modification by (-) sulpiride and (-) pindolol significantly reduced percentage antinociception. The respectively in mice reserpine-induced reduction in the nociceptive No. Treatment (mg/kg) % threshold was reversed by roxindole (4 and 8 mglkg) Antinociception (P 3 Reserpine (2)+Roxindole (4) l2,46±O.78a Discussion The present. study demonstrates that acute a 4 Reserpine (2)+Roxi ndole (8) 23.34±1.36 administration of D2 autoreceptor selective agonist, roxindole produced an antinociceptive response in 5 Reserpine (2)+Sulp iride (50)+Roxindole (4) - 12.93±O.13h mice. Previously, Verma and Kulkarni' (1993) have 6 Reserpine (2)+Sulpiride (50)+Roxindole (8) - I 1. 04±O.78c reported that DA agoni sts such as B-HT 920, bromocriptine and apomorphine produced 7 Reserpine (2)+Pindolol (S)+Roxindole (4) - 13 .09±O.74h 7 antinociception . The antinociceptive response 8 Reserp ine (2)+Pindolol (S)+Roxindole -(8) - IO.41±O,42c elicited by roxindole was blocked by (-) sulpiride, a D2 antagonist and (-) pindolol, a selective 5-HTIA ·P STaTis Ti cal analysis- The data was analyzed using blocked by both (-) sulpiride, a selective O2 one way ANOV A foll owed by student's (-test and antagoni st and (-) pindolol, a 5-HTIA antagonist. It is P<0.05 was considered statist icall y significant. known that 5-HTIA receptors control DA neurotransmission in several brain areas20.21 .22. The 5- Results HTI A agoni st, 8-0H DPAT increases locomotor 2 AIl Till ociceptive effecT of roxindole and its reversal acti vi ty in rats ] .24 . It could be possible that roxindole by (-) sulpiride and (-) pindolol-Roxindole (2-16 can stimulate IDA neurotransmission which intum mg/kg) produced dose-dependent increase in might be responsible for the antinociceptive effect. percentage antinociception with higher doses (8 and But some recent studies have shown that 5-HTIA 16 mg/kg) showing ceili ng effects. Lower doses agoni sts including 8-0H DPAT and flesinoxan, have (0.0 I - I mg/kg) of roxindole did not show apparent inhibitory actions on dopamine 25 an tinocicepti ve effect. (-) Sulpiride (50 mg!kg) and (-) neurotransmission . pindolol (5 mg/kg) bl ocked the anti nociceptive effect The reversmg effect of reserpine-induced of roxindole (2- 16 mg/kg) (P