Biomedical subjects

S K Kulkarni

Publications and source records attributed to S K Kulkarni.

At least 55 records · Page 3Linked to original sources

PubMed2001

Sildenafil-induced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway.

Although several lines of evidence have shown a role of the nitric oxide/cyclic guanosine monophosphate signaling pathway in the nociceptive mechanism, the exact role of the phosphodiesterase (PDE) 5 enzyme via the NO-cGMP pathway is not fully understood in pain response. The present study was aimed at exploring the role of the NO-cGMP pathway in nociceptive conditions in experimental animals. Peripheral nociception was assessed by acetic acid-induced chemonociception or carrageenan-induced hyperalgesia and central nociception was assessed by tail-flick and hot-plate methods. Sildenafil exhibited dose-dependent (1, 2, 5 and 10 mg/kg, i.p.) antinociception in both male and female mice against acetic acid-induced writhing. However, it did not alter the pain threshold in central nociception (5 and 10 mg/kg, i.p.). Local administration of sildenafil (50-200 microg/paw, i.pl) also attenuated carrageenan-induced hyperalgesia. In the peripheral nociceptive reaction (acetic acid-induced chemonociception), the antinociceptive effect of sildenafil (2 mg/kg, i.p.) was enhanced by co-administration of sodium nitroprusside (0.25 mg/kg), and L-arginine (50 mg/kg). Sildenafil-induced analgesia was significantly blocked by methylene blue (1 mg/kg), a guanylate cyclase inhibitor, but was not reversed by L-NAME (10 mg/kg), a nitric oxide synthase inhibitor. But a higher dose of L-NAME (20 mg/kg) significantly reversed sildenafil analgesia. Both of these agents also reversed the facilitatory effect of L-arginine (50 mg/kg) and sodium nitroprusside (0.25 mg/kg) on sildenafil analgesia. These results suggest that sildenafil-induced analgesia is mediated via the inhibition of PDE5. The results also indicate that the guanylate cyclase system is stimulated in the peripheral nociceptive reaction. In conclusion, sildenafil produces antinociception and its effect can be potentiated by sodium nitroprusside and L-arginine, probably through the activation of the NO-cyclic GMP pathway.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2001

Role of cysteinyl leukotrienes in nociceptive and inflammatory conditions in experimental animals.

The leukotrienes are potent inflammatory mediators, which may have a role in inflammatory diseases such as allergic rhinitis, inflammatory bowl disease and asthma. Zafirlukast, a cysteinyl leukotriene receptor antagonist, is claimed to be effective in asthma. However, it is not known whether these leukotrienes are involved in nociceptive and peripheral inflammation. The present study aimed to assess the role of cysteinyl leukotrienes in nociceptive and inflammatory conditions in experimental animals. Central nociception was assessed with tail-flick and hot-plate methods and peripheral nociception was assessed by acetic acid-induced chemonociception in mice. Local administration (intraplantar) of carrageenan-induced hyperalgesia and inflammation, measured by paw withdrawal latency and paw volumes, respectively. Zafirlukast (2.5--20 mg/kg, p.o.) produced a significant and dose-dependent antinociceptive and antiinflammatory effect against acetic acid-induced chemonociception in mice and carrageenan-induced paw oedema in rats, respectively. Zafirlukast (2.5 and 5.0 mg/kg, p.o.) also attenuated the carrageenan-provoked hyperalgesia but did not alter the pain threshold in central nociception up to 20 mg/kg. Zafirlukast (5 and 10 mg/kg ) significantly inhibited exudate formation and migration of polymorphonuclear leukocytes in carrageenan-induced pleurisy. Further, zafirlukast (5 mg/kg) also reduced myeloperoxidase activity in carrageenan-treated paw. When nimesulide (2 mg/kg, p.o.) was co-administered with zafirlukast, the antinociceptive, antihyperalgesic and antiinflammatory effects of nimesulide were significantly increased as compared to the per se effect. The results indicate that cysteinyl leukotrienes are involved in nociceptive/inflammatory conditions. It is expected that combination of cysteinyl leukotriene receptor antagonist with cyclooxygenase inhibitor would prove to be a novel approach to treat complex inflammatory conditions.

Analgesics↗

PubMed2001

Reversal of reserpine-induced vacuous chewing movements in rats by melatonin: involvement of peripheral benzodiazepine receptors.

Several reports have indicated that melatonin modulates striatal dopaminergic functions via its interaction with central and peripheral benzodiazepine (BZ) receptors. Clinical reports and animal studies speculated on the possible involvement of melatonin in the pathophysiology of tardive dyskinesia (TD). In view of this, the present experiment was performed to study the possible effect of melatonin in modulation of reserpine-induced dyskinesia. Melatonin (1-10 mg/kg) dose dependently suppressed the severity of vacuous chewing movements (VCMs) in rats. Prior administration of the putative melatonin receptor antagonists luzindole (2.5 and 5 mg/kg) or prazosin (2.5 and 5 mg/kg) failed to antagonize melatonin (2.5 mg/kg) reversal of reserpine-induced VCMs. However, the peripheral BZ receptor antagonist PK11195 (0.5 and 1 mg/kg) but not flumazenil (1 and 2 mg/kg), dose dependently antagonized melatonin's reversal of reserpine-induced VCMs. Taken together the present results demonstrate that melatonin reverses reserpine-induced VCMs and that this could be due to enhancement of GABAergic activity via peripheral BZ receptors.

Adrenergic Uptake Inhibitors↗

PubMed2001

Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT3 receptor antagonists.

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT3 receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT3 receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT3 receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.

Animals↗

PubMed2001

Possible antioxidant mechanism in melatonin reversal of aging and chronic ethanol-induced amnesia in plus-maze and passive avoidance memory tasks.

Cognitive dysfunction is one of the most striking age-related impairments seen in human beings and animals. This impairment probably is due to the vulnerability of the brain cells to increased oxidative stress during aging process. Pineal hormone melatonin is reported to be an endogenous antioxidant, whose peak plasma level declines during aging and in Alzheimer's disease (AD). Present experiments were performed to study the possible effect of exogenously administered melatonin on cognitive performance of young, aged, or ethanol-intoxicated mice (an animal model for AD) using one trial step-down type of passive avoidance and elevated plus-maze task. Aged or chronic ethanol-treated mice showed poor retention of memory in step-down passive avoidance and in elevated plus-maze task. Chronic administration of melatonin (0.1-10 mg/kg, sc) for 30 d or its coadministration with ethanol (15% W/V, 2 g/kg perorally) for 24 d significantly reversed the age-induced or chronic ethanol-induced retention deficits in both the test paradigms. However, in both the memory paradigms chronic administration of melatonin failed to modulate the retention performance of young mice. Chronic administration of melatonin (0.1-10 mg/kg) for 30 d also reversed age-associated decline in forebrain total glutathione (tGSH) level. Chronic ethanol administration to young mice produced decline in forebrain tGSH level and enhanced brain lipid peroxidation, which was significantly reversed by coadministration of melatonin (10 mg/kg). The results of this study showed chronic melatonin treatment reverses cognitive deficits in aged and ethanol-intoxicated mice, which is associated with its antioxidant property.

Aging↗

PubMed2001

The patello-femoral joint in total knee arthroplasty: is the design of the trochlea the critical factor?

We report the outcome after 10 years of a prospective study of two cohorts of patients undergoing total knee reconstruction treated with patellar replacement (centre A, n = 124) or without (centre B, n = 143). The same tibio-femoral components were used in all knees. The cohorts were demographically similar. The clinical outcome and the patello-femoral revision rates were the same in the two cohorts. Analgesia was required for anterior knee pain in one patient with replacement and in one without. In the replacement group patello-femoral survival on a best-case scenario was 100% at 10 years, and on a worst-case scenario 96%; one of the nonreplaced patellae had been resurfaced for pain by 10 years. In view of the satisfactory and similar outcomes with and without replacement the authors suggest that an appropriate design for the prosthetic trochlea, rather than the replacement or otherwise of the patella, is the main determinant of patello-femoral outcome in total knee reconstruction. Thus patella replacement may be optional. Desirable trochlea design features are described.

Arthroplasty, Replacement, Knee↗

PubMed2001

Investigations on possible serotonergic involvement in effects of OB-200G (polyherbal preparation) on food intake in female mice.

BACKGROUND: OB-200G is a polyherbal preparation containing aqueous extracts of Garcinia cambogia, Gymnema sylvestre, Zingiber officinale, Piper longum and resin from Commiphora mukul, all possessing thermogenic properties. Our previous studies reveal OB-200G to exert antiobesity effects in dietary animal models of obesity. AIM OF THE STUDY: The present study investigated the possible involvement of serotonergic system in the effect of OB-200G on food intake. We examined the effects of systemic pretreatment with 5-HT depletor, p-chlorophenylalanine (PCPA, 300 mg/kg, i. p. for 6 days), 5-HT1A agonist, (8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT, 0.1 mg/kg, i. p.), nonselective 5-HT antagonist, cyproheptadine (1 mg/kg, i. p.), 5-HT2 receptor antagonist, seganserin (1 and 2 mg/kg, i. p.) and 2-deoxy-D-glucose (2-DG, glucose antimetabolite, 500 mg/kg, i. p.) on satiety induced by OB-200G (500 mg/kg, p. o.) in non-deprived female mice. The results were compared with fluoxetine (10 mg/kg, i. p.), a selective serotonin reuptake inhibitor. METHODS: Fifteen minutes after the last drug administration, groups of mice were presented with sweetened chow and the amount of food consumed was recorded at 0.5,1,2, 3 and 4h time intervals. RESULTS: The hyperphagic effect of PCPA, 8-OH-DPAT, cyproheptadine and 2-DG was significantly (p < 0.05) antagonized by both OB-200G and fluoxetine. However, the anorectic effect of fluoxetine was not reversed by centrally acting 5-HT2 antagonist, seganserin but the latter markedly attenuated the satiety action of OB-200G. CONCLUSION: The present observations suggest the role of serotonin in mediation of satiety by OB-200G and hence its antiobesity effect.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2001

Comparative studies on metal biosorption by two strains of Cladosporium cladosporioides.

Two strains of a fungus, Cladosporium cladosporioides 1 and C. cladosporioides 2 showed different metal biosorption properties. Strain 1 showed preferential sorption of gold and silver, while strain 2 could bind metals such as copper and cadmium in addition to gold and silver. Strain 1 had a cell-wall hexosamine content of 0.1%. X-ray photoelectron spectroscopy (XPS) and Fourier transform infra-red spectroscopy (FTIR) analyses indicated that nitrogen was not involved in metal biosorption by the strain. In strain 2 the cell-wall hexosamine content was 150 times that of strain 1. These results indicated that hexosamine was responsible for non-specific metal binding while cell-wall polymers other than hexosamines had a role in conferring selectivity in precious-metal binding.

Absorption↗

PubMed2001

Melatonin enhances Th2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists.

Chronic administration of melatonin for 5 days to antigen-primed mice increased the production of pro-inflammatory cytokine IL-10 but decreased the secretion of anti-inflammatory cytokine TNF-alpha. These results further confirm that melatonin activates Th2-like immune response. Whether melatonin-mediated Th2 response is dependent on opioid or central and peripheral benzodiazepine receptors was also examined. Hence, melatonin was administered to antigen-sensitised mice with either naltrexone (a mu opioid receptor antagonist) or flumazenil (a central benzodiazepine receptor antagonist) or PK11195 (a peripheral benzoidiazepine receptor antagonist). No significant difference in melatonin-induced Th2 cell response was observed by naltrexone, flumazenil or PK11195 treatment. These findings suggest that the Th2 cell response induced by melatonin in antigen sensitised mice neither dependent on endogenous opioid system nor is modulated through the central or peripheral benzodiazepine receptors.

Animals↗

PubMed2001

Melatonin provides signal 3 to unprimed CD4(+) T cells but failed to stimulate LPS primed B cells.

Growing evidence has supported the conclusion that melatonin, a pineal hormone, modulates the immune function. In our previous study, we evaluated in vivo the potential role of melatonin in the regulation of the antigen specific T and B cells. In the present study, we observe that melatonin down-regulated the expression of the co-stimulatory molecule B7-1 but not B7-2 on macrophages. Further, melatonin encouraged the proliferation of anti-CD3 antibody activated CD4(+) T cells only in the presence of antigen-presenting cells and promoted the production of Th2-like cytokines. Furthermore, it failed to influence the activity of B cells in a T-independent manner. Melatonin suppressed the release of TNF-alpha by LPS or IFN-gamma activated macrophages but failed to inhibit nitric oxide (NO) release. Thus the study shows that melatonin can engineer the growth of unprimed CD4(+) T cells if both the signals are provided by antigen-presenting cells. However, it could not regulate the function of B cells.

Animals↗

PubMed2001

Comparative studies on the memory-enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm.

Renin angiotensin system (RAS) in the central nervous system participates in the processing of sensory information, learning and memory processes. Inhibitors of RAS, particularly angiotensin converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor antagonists are reported to have potential nootropic effects in various learning and memory paradigms. The neurochemical basis underlying nootropic effect of ACE inhibitors are unclear due to wide range of substrate for this enzyme. In this study, we compared the effect of ACE inhibitor captopril and a selective AT(1)receptor antagonist losartan in a step-up shock avoidance (active avoidance) task. Captopril (5-10 mg/kg) but not losartan (5-10 mg/kg) improved learning in the second trial of the acquisition test. However, both these drugs were equally effective in enhancing retention of memory when administered prior to training. Retention enhancing effect of captopril and losartan were reversed by post-acquisition test administration of L-NAME (15 mg/kg), dizocilpine (0.05 mg/kg) and scopolamine (0.1 mg/kg). On the basis of above observations, it is concluded that decrease in endogenous Ang II activity in the brain might result in improved cognitive performance by enhancing cGMP pathways. However facilitation of acquisition only by captopril may be due to other putative mechanisms.

Angiotensin Receptor Antagonists↗

PubMed2001

Excitatory mechanisms in neuroleptic-induced vacuous chewing movements (VCMs): possible involvement of calcium and nitric oxide.

Tardive dyskinesia (TD) is a serious motor side-effect of chronic neuroleptic therapy. Chronic treatment with neuroleptics leads to the development of oral abnormal movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats have been widely accepted as an animal model of tardive dyskinesia. Chronic blockade of D2 inhibitory dopamine (DA) receptors localized on glutamatergic terminals in the striatum leads to the persistent enhanced release of glutamate that kills the striatal output neurons. The object of the present study was to explore the role of glutamatergic modulation on the neuroleptic-induced VCMs. Rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to produce VCMs. The neuroleptic-induced VCMs viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5 min observation period. Dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, dose dependently (0.02 and 0.05 mg/kg) reduced haloperidol-induced VCMs. Felodipine (5 and 10 mg/kg), an L-type calcium-channel blocker, also significantly reduced the VCM count. N-omega-nitro-L-arginine methyl ester (L-NAME) (25 and 50 mg/kg), a nitric oxide synthase inhibitor, also reduced the VCM count in an L-arginine-sensitive manner. In conclusion, the findings of the present study indicated NMDA receptor involvement in haloperidol-induced VCMs, and also suggested the possible involvement of calcium and nitric oxide in haloperidol-induced VCMs.

Animals↗

PubMed2001

Subchronic studies on modulation of feeding behavior and body weight by neurosteroids in female mice.

Neurosteroids have shown promising therapeutic potential in a wide variety of neuropsychiatric and cognitive disorders. However, little research has been done on their role for the treatment of eating disorders and regulation of energy balance in the body. In the present study, subchronic treatment with the neuroactive steroid progesterone (10 mg/kg s.c.) for 28 days produced significant increases in body weight and elicited marked hyperphagia as compared to a vehicle-treated control group at all time intervals as observed on days 1, 7, 14, 21 and 28. On the other hand, subchronic treatment with dehydroepiandrosterone sulfate (DHEAS) for 28 days at 10 mg/kg s.c. produced significant (p < 0.05) decreases in body weight and food intake at all time intervals on days 1, 7, 14 and 28 suggesting that decreases in food intake are responsible for the reduction of body weight caused by DHEAS in this strain of female mice. Subchronic treatment with DHEAS (10 mg/kg s.c.) also significantly (p < 0.05) suppressed progesterone-induced weight gain and hyperphagia as compared to the progesterone-treated group but not as compared to the vehicle-treated control group (except on day 1). In conclusion, the results of the present study suggest that progesterone-induced hyperphagia and weight gain can serve as a useful animal model of drug-induced obesity. The drugs useful in this model may have implications for the treatment of obesity caused by disturbances of ovarian hormone secretion in females. Furthermore, the study underscores the use of these neurosteroids for the treatment of eating disorders.

Animals↗

PubMed2001

Lipopolysaccharide-mediated immobility in mice: reversal by cyclooxygenase enzyme inhibitors.

Endotoxin (lipopolysaccharide, LPS) is known to activate the hypothalamo-pituitary adrenocortical axis, as well as norepinephrine and indolamine metabolism. In the present study we examined the effects of systemically administered LPS on forced swimming-induced despair behavior in mice. LPS (50 micrograms/mouse i.p.) time-dependently enhanced the forced swimming-induced immobility period. The increase in immobility time was highest after 2 h of LPS administration. Desipramine (10 mg/kg), a tricycle antidepressant, or fluoxetine (10 mg/kg), a serotonin reuptake inhibitor, significantly reversed the LPS-induced increase in immobility time. Cyclooxygenase inhibitors nimesulide (1, 2 and 5 mg/kg), naproxen (10 mg/kg) and rofecoxib (2 mg/kg) did not alter the despair behavior per se. Nimesulide (10 mg/kg) did reverse reserpine-induced immobility. Nimesulide (2 mg/kg), naproxen (10 mg/kg) and rofecoxib (2 mg/kg) significantly reversed LPS-mediated despair behavior. The present study demonstrated that LPS-induced inflammatory responses in the brain may cause despair behavior. Reversal with a cyclooxygenase inhibitor indicates the role of prostaglandins in despair behavior.

Animals↗

PubMed2001

Animal models of tardive dyskinesia--a review.

Tardive dyskinesia is a serious motor side effect of long term neuroleptic therapy, with an unknown pathophysiological basis. The leading hypothesis of the pathophysiology of tardive dyskinesia includes dopamine receptor supersensitivity, GABAergic hypofunction, excitotoxicity and oxidative stress. Many preclinical models have been developed to identify the underlying pathological processes of tardive dyskinesia, but none has yet produced a parsimonious results. A wide range of animal models, viz. Homologous, analogous and correlational models have been developed to explore the pathophysiology of tardive dyskinesia. Vacuous chewing movements in rodents induced by chronic neuroleptic treatment is the most frequently employed model. As the existing models suffer from several phenomenological and methodological problems, development of new models, highly predictive of pathological basis of tardive dyskinesia can accelerate tardive dyskinesia research for the better understanding of the pathophysiological processes underlying the syndrome and for the discovery of new therapeutic targets for the treatment of tardive dyskinesia.

Animals↗

PubMed2001

Differential effect of polyherbal, antiobesity preparation, OB-200G in male and female mice and monosodium glutamate-treated rats.

Effect of administration of different doses (0.25, 0.5, 1 and 2 g/kg, twice daily, po) of a polyherbal preparation, OB-200G and fluoxetine (10 mg/kg, ip) for 21 days was studied on food intake and body weight in male and female Laka mice. The study further investigated the effect of administration of 0.5 g/kg dose of OB-200G for 40 days on body weight, fat pad weights, locomotor activity and biochemical parameters in monosodium glutamate (MSG)-treated male and female Wistar rat pups. Administration of OB-200G produced dose dependent decrease in body weight in both male and female mice. On the other hand, fluoxetine decreased body weight only in female mice. The food intake was significantly (P < 0.05) increased in both fasted male and female mice after treatment with the lower dose (0.25 g/kg, po) of OB-200G. However, significant (P < 0.05) decrease in food intake was recorded with the administration of higher doses (0.5, 1 and 2 g/kg, po) of OB-200G and fluoxetine in fasted female mice on day 1, 7, 14 and 21. But in male mice differential effect on food intake was recorded at different doses on day 1, 7, 14 and 21. Further, OB-200G administration significantly (P < 0.05) decreased body weight and fat pad weights, increased serum glucose levels and ambulatory activity in MSG-treated female rats but not in MSG-treated male rats. The results suggest that OB-200G involves gender differences in mediating its antiobesity effect and may supplement the current armamentarium for the treatment of obesity.

Adipose Tissue↗

PubMed2000

Possible mechanisms of action in melatonin reversal of morphine tolerance and dependence in mice.

In our earlier study, we reported the ability of melatonin to reverse the development of morphine tolerance and dependence in mice. In the present study, we attempted to analyse the possible involvement of putative melatonin receptors, central and peripheral benzodiazepine receptors and the nitric oxide (NO) system in the mechanism of melatonin reversal of morphine tolerance and dependence in mice. Co-administration of L-N(G)-nitro arginine methyl ester (L-NAME) or melatonin with morphine during the induction phase (days 1-9) delayed the development of tolerance to the anti-nociceptive action of morphine and also reversed naloxone precipitated withdrawal jumpings. L-arginine administration during the induction phase enhanced the development of tolerance to the anti-nociceptive effect of morphine but had no effect on the naloxone-precipitated withdrawal response. During the expression phase (day 10), acute administration of melatonin or L-NAME reversed, whereas L-arginine facilitated, naloxone-precipitated withdrawal jumping in morphine-tolerant mice, but none of these drugs affected the nociceptive threshold in morphine-tolerant mice. Further, co-administration of melatonin or L-NAME with L-arginine during the induction phase antagonized later the effects on the development of morphine tolerance. Also, prior administration of melatonin or L-NAME reversed the L-arginine potentiation of naloxone-precipitated withdrawal jumping in morphine tolerant mice. Among the antagonists for putative melatonin receptors studied, neither luzindole (melatonin MT1 and MT2 receptor antagonist) nor prazosin (melatonin MT3 receptor antagonist) antagonized the melatonin reversal of morphine tolerance and dependence. 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK11195), a peripheral but not central benzodiazepine receptor antagonist, flumazenil, partially antagonized the melatonin reversal of naloxone-precipitated withdrawal jumping in morphine-dependent mice, but had no effect on the reversal of morphine tolerance induced by melatonin. Overall, the present observations suggest that the melatonin-induced reversal of morphine tolerance and dependence may involve its ability to suppress nitric oxide synthase (NOS) activity. Further, the melatonin-induced reversal of morphine tolerance and dependence is not mediated through its actions via putative melatonin receptors. The agonistic activity of melatonin towards peripheral benzodiazepine receptors may partially contribute to the suppression of morphine dependence but not to the reversal of tolerance to the analgesic activity of morphine.

Animals↗

PubMed2000

Ketanserin reverses dizocilpine-suppression of morphine dependence but not tolerance in mice.

The present study investigated the effect of co-administration of ketanserin, a 5-HT(2A) receptor antagonist and dizocilpine, a non-competitive NMDA receptor antagonist on the development of tolerance and dependence to morphine in mice. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg, twice daily) on day 3 and the degree of tolerance was further enhanced on day 9 and 10. Dizocilpine (0.2 mg/kg, twice daily for 9 days) prevented the development of tolerance to the antinociceptive effect of morphine. Dizocilpine (0.2 mg/kg) or combination of dizocilpine (0.2 mg/kg) and ketanserin (0.5, 1 and 2 mg/kg) acutely on day 10 did not affect morphine tolerance. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) pre-treatment failed to reverse the effect of dizocilpine on morphine tolerance. Dizocilpine (0.2 mg/kg, twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal jumps and diarrhea on day 10 of testing. Similarly, dizocilpine (0.2 mg/kg) acutely on day 10 suppressed the development of morphine dependence. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days and acutely on day 10) pre-treatment reversed the effect of dizocilpine on morphine dependence. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) did not affect development of morphine tolerance and dependence. The present study demonstrated that ketanserin, a 5-HT(2A) receptor antagonist reversed the effect of dizocilpine on morphine dependence. This study gives behavioral evidence to the hypothesis that 5-HT(2A) receptor antagonists facilitate NMDA neurotransmission.

Animals↗