sch-23390 and Pain

The lateral hypothalamus (LH) is one of the key brain areas involved in pain modulation. Also, the dentate gyrus (DG) of the hippocampus expresses various receptors, including dopaminergic receptors. Dopaminergic receptors play a key role in pain transmission and modulation within the brain. The present study aimed to investigate the involvement of DG dopaminergic receptors in the LH-induced antinociception during the presence of inflammatory pain. Male Wistar rats were used in this study. Cannulae were unilaterally implanted in their skull for microinjections into the LH and DG. The LH was chemically stimulated by carbachol injection (250 nM/0.5 μl saline). In separate groups, different doses (0.25, 1, and 4 μg/0.5 μl vehicle) of the D1- and D2-like dopamine receptor antagonists (SCH23390 and Sulpiride, respectively) were microinjected into the DG, 5 min prior to intra-LH injection of carbachol. Five min after the second injection, formalin test as a persistent inflammatory pain model in animals was done in all rats. The results revealed that carbachol could induce antinociception following formalin injection into rat's hind paw. The 4 μg dose of both antagonists significantly reduced the LH stimulation-induced antinociception in both phases of formalin pain responses. Although the 1 μg dose of sulpiride significantly reduced antinociception during both phases, 1 μg SCH23390 could only reduce this antinociception during the late phase. These findings demonstrate the involvement of DG dopaminergic receptors in the LH-induced antinociception. The results also suggest that the effectiveness of DG dopaminergic receptors is more pronounced during the late phase of formalin-induced pain responses.

Topics: Analgesics; Analgesics, Non-Narcotic; Animals; Benzazepines; Carbachol; Dentate Gyrus; Dopamine Antagonists; Dopaminergic Neurons; Hypothalamic Area, Lateral; Male; Nociception; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Dopamine; Sulpiride

The ability to modulate pain perception is as critical to survival as pain itself. The most known pain modulation pathway is the PAG-RVM (periaqueductal gray-rostral ventromedial medulla) descending system. In this study, we hypothesized that it is functionally linked to the ascending nociceptive control, which is a form of pain-induced analgesia dependent on mesolimbic mechanisms. To test this hypothesis, we used a pharmacological approach, in which the antinociception induced by noxious stimulation (forepaw injection of capsaicin) was detected in a standard rat model of inflammatory pain (hindpaw injection of carrageenan). This antinociception was blocked by interventions known to block the ascending nociceptive control-mediated analgesia: the blockade of μ-opioid (Cys

Topics: Analgesia; Analgesics, Opioid; Animals; Benzazepines; Lidocaine; Male; Medulla Oblongata; Pain; Pain Management; Pain Measurement; Periaqueductal Gray; Rats, Wistar; Receptors, Opioid, mu; Somatostatin

Lateral hypothalamus (LH) involves in modulation of tonic pain. Regarding the direct and indirect neural connections between the LH and nucleus accumbens (NAc), we aimed to examine the pain modulatory role of NAc dopamine receptors in modulation of LH-induced analgesia in the formalin test.. Vehicle-control groups received saline or DMSO into the NAc and saline into the LH. Carbachol-control groups received carbachol (250 nmol/L) into the LH, 5 min after saline or DMSO injection into the NAc. In treatment groups, intra-NAc administration of SCH-23390 or sulpiride (D1-and D2-like dopamine receptor antagonists, respectively) was performed 5 min before carbachol injection. Formalin test was done in all rats 5 min after the second injection.. The blockade of NAc dopamine receptors reduced carbachol-induced antinociception during both phases of formalin test and reduction in LH-induced analgesia during the late phase was more than that during the early phase. Furthermore, contribution of D2-like dopamine receptors to mediation of anti-hyperalgesic effect of carbachol was greater than that of D1-like dopamine receptors during the late phase.. The findings suggest that LH-VTA-NAc circuit is contributed to the modulation of formalin-induced pain. These findings demonstrate that transmission at D1- and D2-like dopamine receptors mediates the LH-induced analgesia.. Blockade of accumbal dopamine receptors attenuated analgesia induced by carbachol injection into the lateral hypothalamus during both phases of formalin test. Effect of blockade of D1- and D2-like dopamine receptors on reduction in antinociception was more during the late phase. Contribution of D2-like dopamine receptors to mediation of antinociception during the late phase was greater than the early phase.

Topics: Analgesia; Animals; Benzazepines; Carbachol; Hypothalamus; Male; Nucleus Accumbens; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Dopamine; Sulpiride

Stressful experiences can produce analgesia, termed stress-induced analgesia (SIA). Meanwhile, it has been widely established that the mesolimbic dopamine pathway and nucleus accumbens (NAc) have a profound role in pain modulation. In this study, we examined the role of accumbal dopamine receptors in antinociception caused by forced swim stress (FSS) in order to understand more about the function of these receptors within the NAc in FSS-induced analgesia.. Stereotaxic surgery was unilaterally performed on adult male Wistar rats weighing 230-250 g (some on the left and some on the right side of the midline). Two supergroups were microinjected into the NAc with a D1-like dopamine receptor antagonist, SCH-23390, at doses of 0.25, 1 and 4 μg/0.5 μl saline per rat or Sulpiride as a D2-like dopamine receptor antagonist at the same doses [0.25, 1 and 4 μg/0.5 μl dimethyl sulfoxide (DMSO) per rat]; while their controls just received intra-accumbal saline or DMSO at 0.5 μl, respectively. The formalin test was performed after rats were subjected to FSS (6 min, 25 ± 1 °C) to assess pain-related behaviours.. The results demonstrated that intra-accumbal infusions of SCH-23390 and Sulpiride dose-dependently reduced FSS-induced antinociception in both phases of the formalin test. However, the percentage decrease in area under the curve (AUC) values calculated for treatment groups compared to formalin-control group was more significant in the late phase than the early phase.. Our findings suggest that D1- and D2-like dopamine receptors in the NAc are involved in stress-induced antinociceptive behaviours in the formalin test as an animal model of persistent inflammatory pain.. Forced swim stress (FSS) induces the antinociception in both phases of formalin test. Blockade of accumbal dopamine receptors attenuate the antinociception induced by FSS. Stress-induced analgesia is dose-dependently reduced by dopamine receptor antagonists in both phases, although it is more prominent during the late phase.

Topics: Analgesia; Animals; Benzazepines; Dopamine; Dopamine Antagonists; Formaldehyde; Male; Nucleus Accumbens; Pain; Pain Management; Pain Measurement; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulpiride

It was established that stimulation of the lateral hypothalamus (LH) can induce antinociception. Previous studies showed a role for the ventral tegmental area (VTA) and nucleus accumbens (NAc) in antinociception induced by LH stimulation through the orexinergic system. In this study, we tried to assess the involvement of dopamine D1-like receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA or intra-accumbal infusion of SCH-23390, as a D1-like dopamine receptor antagonist (0.125, 0.25, 1 and 4 μg/rat), 2 min before intra-LH administration of carbachol (125 nM/rat). The antinociceptive effects of SCH-23390 were measured by using a tail-flick analgesiometer and represented as maximal possible effect (%MPE). Results showed that intra-VTA and/or accumbal administration of SCH-23390 could prevent carbachol-induced antinociception. These findings revealed that D1-like dopamine receptors within the VTA and NAc play an important role in antinociceptive effect induced by chemical stimulation of the LH.

Topics: Analgesics; Animals; Benzazepines; Carbachol; Hypothalamus; Intracellular Signaling Peptides and Proteins; Male; Neuropeptides; Nucleus Accumbens; Orexin Receptors; Orexins; Pain; Rats, Wistar; Receptors, Dopamine D1; Synapses; Ventral Tegmental Area

Affections are thought to regulate pain perception through the descending pain inhibitory system in the central nervous system. In this study, we examined in mice the affective change by inhalation of the lemon oil, which is well used for aromatherapy, and the effect of lemon odor on pain sensation. We also examined the anterior cingulate cortex (ACC) and descending pain inhibitory system to such regulation of pain.. In the elevated plus maze, the time spent in the open arms was increased by inhalation of lemon oil. The pain behavior induced by injection of formalin into the hind paw was decreased. By inhalation of lemon oil, the number of c-Fos expression by formalin injection was significantly increased in the ACC, periaqueductal grey (PAG), nucleu raphe magnus (NRM) and locus ceruleus, and decreased in the spinal dorsal horn (SDH). The destruction of the ACC with ibotenic acid led to prevent the decrease of formalin-evoked nocifensive behavior in mice exposed to lemon oil. In these mice, the change of formalin-induced c-Fos expression in the ACC, lateral PAG, NRM and SDH by lemon odor was also prevented. Antagonize of dopamine D1 receptor in the ACC prevented to the analgesic effect of lemon oil.. These results suggest that the analgesic effect of lemon oil is induced by dopamine-related activation of ACC and the descending pain inhibitory system.

Topics: Administration, Inhalation; Affect; Animals; Aromatherapy; Benzazepines; Disease Models, Animal; Dopamine Antagonists; Excitatory Amino Acid Agonists; Exploratory Behavior; Formaldehyde; Gyrus Cinguli; Ibotenic Acid; Maze Learning; Mice; Mice, Inbred ICR; Neural Pathways; Odorants; Pain; Pain Measurement; Plant Oils

While opioid receptors have been implicated in the development of tolerance, the subsequent mechanisms involved in these phenomena have not been completely understood. The purpose of this study was to investigate effects of D1/D2 dopamine receptors antagonist perphenazine on morphine analgesia and tolerance in rats. Male Wistar albino rats weighing 190-205 g were used in these experiments. To constitute of morphine tolerance, animals received morphine (50 mg/kg) once daily for 3 days. After last dose of morphine was injected on day 4, morphine tolerance was evaluated by the analgesia tests. The analgesic effects of perphenazine (1, 5, and 10 mg/kg ), D1-dopamine receptor antagonist SCH 23390 (1 mg/kg), D2-dopamine receptor antagonist eticlopride (1 mg/kg), and morphine were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Obtained data suggested that D1/D2 dopamine receptors antagonist perphenazine was capable of suppressing opioid tolerance, possibly by the mechanism of inhibiting D2-dopamine receptor. Because the data indicated that D2-dopamine receptor antagonist eticloride, but not D1-dopamine receptor antagonist SCH 23390, significantly decreased morphine tolerance in analgesia tests. In addition, administration of perphenazine with morphine increased morphine analgesia. Results from the present study suggested that dopamine receptors play a significant role in the morphine analgesic tolerance. In particular, D2-dopamine receptor has an important role rather than D1-dopamine receptor in development tolerance to morphine.

Topics: Analgesia; Animals; Benzazepines; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Tolerance; Male; Morphine; Pain; Perphenazine; Rats; Rats, Wistar; Receptors, Dopamine D1; Salicylamides; Time Factors

Previous studies showed the role of basolateral amygdala (BLA) in cannabinoid-induced antinociception. Furthermore, the nucleus accumbens (NAc) plays an important role in mediating the suppression of pain in animal models. The present study extended the role of dopamine receptors within the NAc in antinociceptive effect of cannabinoid receptor agonist, WIN55,212-2, microinjected into the BLA following the tail-flick and formalin tests in rats. In this study, 174 adult male albino Wistar rats were unilaterally implanted by two separate cannulae into the BLA and NAc. In two separated groups, rats received intra-NAc infusions of the D1 receptor antagonist, SCH-23390 (0.25, 1 and 4 μg/0.5 μl saline) or D2 receptor antagonist, sulpiride (0.25, 1 and 4 μg/0.5 DMSO), and just 2 min later, WIN55,212-2 (15 μg/rat) was microinjected into the BLA. In the tail-flick test, antinociceptive responses of drugs represented as maximal possible effect (%MPE) in 5, 15, 30, 45 and 60min after their administrations. Moreover, in the formalin test, pain related behaviors were monitored in 5-min blocks for 60 min test period. Our findings showed that intra-accumbal SCH-233909 dose-dependently prevented antinociception induced by intra-BLA administration of WIN55,212-2 (15 μg/rat) in time set intervals in formalin, but not tail-flick test. Besides, administration of sulpiride in the NAc could affect WIN-induced analgesia in both models of pain. In conclusion, it seems that D2 receptors located in the NAc, in part, mediate the antinociceptive responses of cannabinoid within the BLA, while D1 receptors only are involved in modulation of persistent inflammatory model of pain.

Topics: Amygdala; Analysis of Variance; Animals; Benzazepines; Benzoxazines; Cannabinoid Receptor Agonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Male; Microinjections; Morpholines; Naphthalenes; Nucleus Accumbens; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Dopamine D1; Sulpiride; Time Factors

The objective of this study was to extend our previous findings by investigating in greater detail the mechanisms that might be involved in the antinociceptive action of p-methoxyl-diphenyl diselenide, (MeOPhSe)(2), in mice. The pretreatment with nitric oxide precursor, l-arginine (600 mg/kg, intraperitoneal, i.p.), reversed antinociception caused by (MeOPhSe)(2) (10 mg/kg, p.o.) or N(G)-nitro-l-arginine (l-NOARG, 75 mg/kg, i.p.) in the glutamate test. Ondansetron (0.5 mg/kg, i.p., a 5-HT(3) receptor antagonist) and SCH23390 (0.05 mg/kg, i.p.., a D(1) receptor antagonist) blocked the antinociceptive effect caused by (MeOPhSe)(2). Conversely, pindolol (1 mg/kg, i.p., a 5-HT(1A)/(1B) receptor/beta adrenoceptor antagonist), WAY 100635 (0.7 mg/kg, i.p., a selective 5-HT(1A) receptor antagonist), ketanserin (0.3 mg/kg, i.p., a selective 5-HT(2A) receptor antagonist), prazosin (0.15 mg/kg, i.p., an alpha(1)-adrenoreceptor antagonist), yohimbine (1.0 mg/kg, i.p., an alpha(2)-adrenoreceptor antagonist), sulpiride (5 mg/kg, i.p., a D(2) receptor antagonist), naloxone (1 mg/kg, i.p., a non-selective opioid receptor antagonist) and caffeine (3 mg/kg, i.p., a non-selective adenosine receptor antagonist) did not change the antinociceptive effect of (MeOPhSe)(2). (MeOPhSe)(2) significantly inhibited nociception induced by intraplantar (i.pl.) injection of bradykinin (10 nmol/paw) and Des-Arg(9)-bradykinin (10 nmol/paw, a B(1) receptor agonist). (MeOPhSe)(2) significantly inhibited phorbol myristate acetate (PMA, 0.03 mug/paw, a protein kinase C (PKC) activator)-induced licking response. These results indicate that (MeOPhSe)(2) produced antinociception in mice through mechanisms that involve an interaction with nitrergic system, 5-HT(3) and D(1) receptors. The antinociceptive effect is related to (MeOPhSe)(2) ability to interact with kinin B(1) and B(2) receptors and PKC pathway mediated mechanisms.

Topics: Analgesics; Animals; Arginine; Benzazepines; Benzene Derivatives; Bradykinin; Dopamine Antagonists; Enzyme Inhibitors; Glutamic Acid; Magnetic Resonance Spectroscopy; Male; Mice; Neurotransmitter Agents; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Organoselenium Compounds; Pain; Receptors, Neurotransmitter; Tetradecanoylphorbol Acetate

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship