Influence of antineoplastic drugs on morphine analgesia and on morphine tolerance

The possible influence of cisplatin, methotrexate, adriamycin and vincristine on thermal pain threshold, morphine analgesia and development of morphine tolerance was investigated in mice. In the hot-plate test, the nociceptive threshold was not affected by acute or repeated administration of any of the antineoplastic drugs used. The analgesic activity of morphine was significantly reduced by pretreatment with cisplatin, intraperitoneally (i.p.) injected at the dose of 2 mg/kg. In contrast, methotrexate, subcutaneously (s.c.) injected at the dose of 1 and 5 mg/kg, adriamycin (1 and 3 mg/kg s.c.), vincristine (0.25 and 0.5 mg/kg i.p.) and a lower dose of cisplatin (1 mg/kg i.p.) had no effect. The development of tolerance to morphine analgesia was delayed by adriamycin but was not influenced by the other antineoplastic drugs used. These data show that, of the four antineoplastic agents used in this study, cisplatin may interfere in the mechanism of action of morphine, and that adriamycin may delay the development of opiate tolerance.     

The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain

We have tested for anti-nociceptive effects of the anticonvulsant KCNQ channel opener, N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester (retigabine), in rat models of experimental pain. In the chronic constriction injury and spared nerve models of neuropathic pain, injection of retigabine (5 and 20 mg/kg, p.o.) significantly attenuated (P<0.05) mechanical hypersensitivity in response to pin prick stimulation of the injured hindpaw. In contrast, retigabine had no effect on mechanical hypersensitivity to von Frey stimulation of the injured hindpaw in either model. Cold sensitivity in response to ethyl chloride was only attenuated (P<0.05) in the chronic constriction injury model. In the formalin test, retigabine (20 mg/kg, p.o.) attenuated flinching behaviour in the second phase compared with vehicle (P<0.05), and this effect was completely reversed by the KCNQ channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991; 3 mg/kg, i.p.). Neither retigabine nor XE-991 administration affected the latency to respond to noxious thermal stimulation of the tail in control animals. These results suggest that retigabine may prove to be effective in the treatment of neuropathic pain.     

Modification of formalin-induced nociception by different histamine receptor agonists and antagonists.

The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20-40 microg/mouse i.c.v.) or subcutaneous (1-10 mg/kg s.c.) injection of HTMT (H(1) receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H(1) receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 mug/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H(2) receptor agonist, 30 mg/kg i.p.) and ranitidine (H(2) receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H(3) receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H(3) receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetit-induced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H(3) receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H(1) and H(3) receptor activations increase sensitivity to nociceptive stimulus in the formalin test.     

Kininogenase activity of Thalassophryne nattereri fish venom

Accidents caused by the venomous fish Thalassophryne nattereri are characterized by edema, intense pain and necrosis at the site of the sting. This study assessed the nociceptive and edematogenic activities of T. nattereri venom after injection into the mouse hindpaw and determination of the paw licking duration and weight. Subplantar injections of the venom (0.1-6 microg) induced a dose-related increase of the paw licking time and paw swelling with maximal values at 3 microg (209.5 +/- 57.5 s and 135.0 +/- 6.8 mg, respectively). Pretreatment of mice with either indomethacin (10 mg/kg, i.p.), a cyclooxygenase inhibitor, dexamethasone (1 mg/kg, s.c.), a steroid anti-inflammatory agent, cyproheptadine (1 mg/kg, i.p.), antagonist of serotonin receptors or L-NAME (100 mg/kg, s.c.), inhibitor of nitric oxide syntase, did not affect the venom-induced nociceptive and edematogenic responses. Injection of the opioid analgesic fentanyl (0.1 mg/kg, s.c.) reduced the paw licking time induced by 1 microg venom by 84% of control, without affecting the paw swelling. Both nociceptive and edematogenic responses were reduced after treatment with a specific tissue kallikrein inhibitor (TKI, 100 mg/kg, i.p.) by 78% and 24% from control values, respectively. Administration of a specific plasma kallikrein inhibitor (PKSI(527,) 100 mg/kg, s.c.) did not affect the venom-induced nociceptive response, but it decreased the paw edema by 15% from control. After injection of the angiotensin-converting enzyme inhibitor captopril (100 mg/kg, i.p.) the venom-induced nociceptive end edematogenic responses were increased by two-fold. The role of kallikreins possibly present in the venom was further assessed by hydrolysis of human kininogen and kininogen-derived synthetic peptides, showing the release of kallidin (Lys-bradykinin). The hydrolysis was inhibited by metal chelating agents but not by serino-, aspartyl- or cysteino-proteinase inhibitors. The data suggest that a protease with tissue-kallikrein-like activity plays a major role in nociception and edema induced by T. nattereri venom and this should be considered to achieve efficient treatments for human accidents with this venom.     

Behavioural analysis of changes in nociceptive thresholds produced by remoxipride in sheep and rats

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores. However, in rats, the dose of remoxipride (100 mg/kg i.p.) required to produce nociceptive thresholds similar to those elicited by morphine (30 mg/kg i.p.), itself reduced rotarod performance. Medetomidine (200 μg/kg i.p.) evoked sedation without influencing rotarod performance or antinociception. The antinociceptive, motor deficit and cataleptogenic actions of remoxipride were similar to those induced by two other dopamine antagonists, haloperidol (5 mg/kg) and raclopride (16 mg/kg i.p). Tocainide (100 mg/kg i.p.) induced thermal antinociception with normal rotarod performance and no catalepsy suggesting that Na⁺ channel blockade by remoxipride is not responsible for the changes in nociceptive thresholds. This study emphasizes the importance of motor function assessment during acute antinociceptive testing.     

Zonisamide suppresses pain symptoms of formalin-induced inflammatory and streptozotocin-induced diabetic neuropathy

We evaluated the effects of zonisamide on inflammatory and neuropathic pain using the mouse formalin test and streptozotocin (STZ)-induced diabetic mice with a reduced withdrawal threshold to mechanical stimuli, respectively. When administered systemically (subcutaneously, s.c.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) before formalin injection, zonisamide (3 and 10 mg/kg, s.c., 10 and 30 microg, i.c.v., or i.t.) significantly reduced licking/biting behavior during the second phase of the formalin test in a dose-dependent manner. However, zonisamide (30 microg, i.t.) did not affect the second phase of the formalin test when given after the first phase, suggesting that it can prevent the development of injury-induced hyperexcitability of the spinal dorsal horn triggered by the repetitive nociceptive input during the first phase. Moreover, zonisamide administered into the dorsal hindpaw ipsilateral but not contralateral to the formalin injection partly reduced the second phase. Thus it is likely that zonisamide generates analgesic effects in the formalin test via both central and peripheral mechanisms. In mice with STZ-induced diabetes, zonisamide (10 and 30 mg/kg, s.c. or 10 and 30 mug, i.t.) reversed the mechanical hyperexcitability. Our results suggest that zonisamide can be a useful therapeutic agent, presumably for both prevention and reversal of pathophysiologic pain.     

Ketamine-induced potentiation of morphine analgesia in rat tail-flick test: role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels

Ketamine is known to improve opioid efficacy, reduce postoperative opioid requirement and oppose opioid associated pain hypersensitivity and tolerance. However, the mechanisms underlying these beneficial effects are not clear. This study investigated the effects of ketamine at a non-analgesic dose (30 mg/kg, i.p.) on analgesia induced by morphine (2.5, 5.0, 7.5 mg/kg, s.c.), using rat tail-flick test as an animal model of acute pain. Further, the role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels was examined on the potentiating effect of ketamine. Male rats received morphine alone at 5.0 and 7.5 but not at 2.5 mg/kg showed a dose-related increase in tail-flick latencies. The combination of morphine and ketamine resulted in dose-related increase in morphine analgesia, both on the intensity as well as on duration. The ketamine-induced potentiation of morphine (7.5 mg/kg) analgesia was unaffected by glibenclamide (3 mg/kg, s.c.) and only partially blocked by yohimbine (2 mg/kg, i.p.), but more completely abolished by naloxone (2 mg/kg, i.p.). Both morphine (5.0 mg/kg) and ketamine (30 mg/kg) alone did not evoke catalepsy in rats but on combination produced a synergistic effect, which was however, abolished by naloxone pretreatment. In the open-field test, while morphine (5.0 mg/kg) caused a depressant effect, ketamine (30 mg/kg) enhanced the locomotor activity. Nevertheless, in combination potentiated the morphine's depressant effect on locomotion, which was also antagonized by naloxone. These results indicate that ketamine at a non-analgesic dose can potentiate morphine analgesia, induce catalepsy and cause locomotor depression, possibly involving an opioid mechanism. This potentiation, although favorable in acute pain management, may have some adverse clinical implications.     

Role of endocannabinoid and glutamatergic systems in DOI-induced head-twitch response in mice

We previously reported that systemic administration of the endocannabinoid anandamide inhibited the head-twitches induced by the hallucinogenic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice, which is mediated via the activation of 5-HT_2A receptors. Endocannabinoid and glutamatergic systems have been suggested to modulate the function of 5-HT_2A receptors. In the present study, we further investigated the role of endocannabinoid and glutamatergic systems in DOI-induced head-twitch response in mice. An anandamide transport inhibitor AM404 (0.3-3 mg/kg, i.p.), a fatty acid amide hydrolase inhibitor URB597 (0.1-10 mg/kg, i.p.), a glutamate release inhibitor riluzole (0.3 and 1 mg/kg, i.p.), a natural glutamate analog l-glutamylethylamide (theanine, 1 and 3 mg/kg, p.o.) and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist NBQX (0.01-0.3 mg/kg, i.p.) significantly inhibited DOI-induced head-twitch response. The AMPA receptor positive modulator aniracetam (30 or 100 mg/kg, p.o.) reversed inhibition of head-twitch response by NBQX and URB597. These findings indicated that endocannabinoid and glutamatergic systems participate in the mechanism of action of DOI to induce head-twitch response.     

B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice

The effect of some B vitamins in chemical and thermal models of nociception in mice was investigated. The association thiamine/pyridoxine/cyanocobalamin (TPC, 20-200 mg/kg, i.p. or per os), thiamine, pyridoxine (50-200 mg/kg, i.p.) or riboflavin (3-100 mg/kg, i.p) induced an antinociceptive effect, not changed by naloxone (10 mg/kg, i.p.), in the acetic acid writhing model. Treatment for 7 days with thiamine/pyridoxine/cyanocobalamin (100 or 200 mg/kg, i.p.), thiamine (50 or 100 mg/kg) or pyridoxine (50 or 100 mg/kg) or acute treatment with riboflavin (6 or 12 mg/kg, i.p) inhibited the nociceptive response induced by formaldehyde. The B vitamins did not inhibit the nociceptive response in the hot-plate model. Both 7-day thiamine/pyridoxine/cyanocobalamin (100 mg/kg, i.p.) or acute riboflavin (25 or 50 mg/kg, i.p.) treatment partially reduced formaldehyde-induced hindpaw oedema. The B vitamins antinociceptive effect may involve inhibition of the synthesis and/or action of inflammatory mediators since it was not observed in the hot-plate model, was not reversed by naloxone, only the second phase of the formaldehyde-induced nociceptive response was inhibited, and formaldehyde-induced hindpaw oedema was reduced.     

Morphine inhibits dopaminergic and cholinergic induced ejaculation in rats

1. Subcutaneous injection (s.c.) of apomorphine (0.1–0.5 mg/kg) and intraperitoneal administration (i.p.) of quinpirole (0.01–0.25 mg/kg), physostigmine (0.05–0.2 mg/kg) and philocarpine (0.75–3 mg/kg, i.p.) but not neostigmine (0.1–1 mg/kg) induced ejaculation in rats.2. The responses of drugs were reduced by morphine (1–6 mg/kg, s.c.) pretreatment.3. The inhibitory effect of morphine was reversed by naloxone (1.5 mg/kg, s.c.).4. Naloxone (0.75–3 mg/kg, s.c.) alone induced slight but significant ejaculation.5. Ejaculatory responses induced by apomorphine and quinpirole but not those by physostigmine and pilocarpine were reduced by sulpiride (100 mg/kg, i.p.) pretreatment.6. Domperidone (1–30 mg/kg, i.p.) did not change the response induced by apomorphine.7. Pretreatment of animals with the cholinergic antagonist atropine (10 mg/kg, i.p.) decreased the frequency of ejaculation induced by apomorphine, quinpirole, physostigmine or pilocarpine.8. It may be concluded that D-2 activation induces ejaculation through influence on cholinergic mechanisms and morphine inhibits the ejaculation induced by activation of both cholinergic and dopaminergic systems via opiate receptor sites.     

Clonidine and guanfacine-induced antinociception in visceral pain: possible role of alpha 2/I2 binding sites

Visceral pain is one of the most common forms of pain which is poorly understood. We now studied the influence of imidazoline/guanidinium compounds such as clonidine and guanfacine on visceral pain in the presence or absence of yohimbine and benazoline. To produce visceral pain-related behaviours, formalin (10%) was administered by inserting a fine cannula into the colon via the anus. Each experiment took 1 h. Clonidine (0.001, 0.01 and 0.1 mg/kg, i.p.) and guanfacine (2.5, 5 and 10 mg/kg, i.p.) produced analgesia dose dependently. The clonidine response was inhibited by yohimbine (0.2 mg/kg, i.p.). On the other hand, benazoline (5 mg/kg, i.p.) blocked the antinociceptive effect of guanfacine (5 mg/kg). Benazoline (2.5 and 5 mg/kg) itself also induced analgesia in inflammatory colonic pain. In this study, we used morphine to ensure that the behavioural responses were pain-related. Our results showed that morphine (2.5, 5 and 10 mg/kg, s.c.) produced a dose-dependent antinociception. The morphine (7 mg/kg, s.c.) response was reduced by naloxone (2 mg/kg, i.p.). However, we concluded that both imidazoline (I(2)) and alpha(2)-adrenoceptors may play a role in producing analgesia in visceral pain.     

Blockade of the metabotropic glutamate 2/3 receptors enhances social memory via the AMPA receptor in rats

The present study examined the role of mGlu(2/3) receptors in short-term social memory using the social recognition paradigm in rats in which an adult rat is exposed to the same juvenile rat in two successive interactions. Intraperitoneal administration of the mGlu(2/3) receptor antagonist MGS0039 (0.3-3 mg/kg) or the ampakine CX546 (0.3-3 mg/kg) significantly and dose-dependently reduced the adult rat's social investigation of the same juvenile rat during the second encounter which occurred 120 min after the first encounter, indicating that both MGS0039 and CX546 enhanced social recognition. Pretreatment with the AMPA receptor antagonist NBQX (0.1-1 mg/kg, s.c.) significantly attenuated the effects of MGS0039 (3 mg/kg, i.p.) in the social recognition test. These results suggest that the mGlu(2/3) receptor blockade increases social recognition memory, presumably through stimulation of the AMPA receptor.     

The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol

Tramadol is an atypical analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of noradrenaline (NA) and serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at micro-opioid receptors. Here, we present data for the novel compound NS7051, which was shown to have sub-micromolar affinity (Ki=0.034microM) for micro-opioid receptors and inhibited reuptake of 5-HT, NA and DA (IC(50)=4.2, 3.3 and 3.5microM in cortex, hippocampus and striatum respectively). NS7051 (1-30mg/kg, s.c.) produced a dose-dependent naloxone-reversible increase in the hot plate withdrawal latency, and was also analgesic in the tail flick test. In models of persistent and chronic inflammatory nociception, NS7051 reversed flinching behaviours during interphase and second phase of the formalin test (ED(50)=1.7 and 1.8mg/kg, s.c.), and hindpaw weight-bearing deficits induced by complete Freund's adjuvant injection (ED50=1.2mg/kg, s.c.). In the chronic constriction injury model of neuropathic pain, mechanical allodynia and hyperalgesia were both reversed by NS7051 (ED50=6.7 and 4.9mg/kg, s.c.). Tramadol was also active in all pain models although at considerably higher doses (20-160mg/kg, s.c.). No ataxia was observed at antiallodynic doses giving therapeutic indices of 19 and 3 for NS7051 and tramadol. The combined opioid receptor agonism and monoamine reuptake inhibitory properties of NS7051 inferred from behavioural studies appear to contribute to its well tolerated antinociceptive profile in rats. However, unlike tramadol this did not correlate with the ability to increase hippocampal monoamine levels measured by microdialysis in anesthetised rats.     

Repeated administration of nicotine attenuates the development of morphine tolerance and dependence in mice

Clinical use of morphine in pain management is a controversial issue. Both nicotine and morphine are widely abused. So, investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical view. We investigated the influence of repeated administration of nicotine on the development of morphine tolerance and dependence. Adult male albino mice were rendered dependent on morphine by subcutaneous (s.c.) injections three times daily for 3 days. Repeated intraperitoneal (i.p.) injection of nicotine (0.001-2 mg/kg) or saline (1 ml/kg) was performed 15 min prior to each morphine injection. Maximal possible effect (MPE%) of morphine (50 mg/kg; s.c.) was used on the fourth day as an index for the development of tolerance. Likewise, to assess the occurrence of dependence in drug-treated mice, naloxone (5 mg/kg; i.p.) was injected 2 h after the last dose of morphine. Repeated nicotine administration significantly attenuated the development of tolerance in a dose-dependent manner whereas it significantly decreased withdrawal jumping behavior in a biphasic profile (V-shape) manner. Furthermore, the central nicotinic receptor antagonist mecamylamine (0.01-0.1 mg/kg; i.p.) neither the peripheral nicotinic receptor antagonist hexamethonium (0.01 and 0.1 mg/kg; i.p.) nor the muscarinic receptor antagonist atropine (2.5-10 mg/kg; i.p.), dose-dependently antagonized both the inhibition of withdrawal jumping as well as increase in MPE% which was produced by repeated nicotine administration (0.1 mg/kg; i.p.). On the other hand, 3 days of solely nicotine treatment resulted in significant jumping behavior precipitated by naloxone after single morphine injection on the test day. The data suggests that the inhibitory effect of nicotine on the morphine tolerance and dependence is mediated by central nicotinic receptors and there is a cross-dependence between nicotine and morphine.     

Lack of cross-sensitization of the locomotor effects of morphine in amphetamine-treated rats.

Repeated exposure to morphine and amphetamine induces long-lasting sensitization of their psychomotor stimulant properties, whereas pretreatment with morphine causes cross-sensitization of the locomotor effects of amphetamine. Here, we investigated whether pre-exposure to amphetamine also results in cross-sensitization to morphine. Rats pretreated with amphetamine (5 x 2.5 mg/kg, i.p.) displayed neither short-term (3 days post-treatment) nor long-term (3 weeks post-treatment) cross-sensitization of the locomotor effects of morphine (2 or 5 mg/kg, s.c.). Two other amphetamine pretreatment protocols (1 x 5 mg/kg, i.p. and 14 x 2.5 mg/kg, i.p.) also failed to induce cross-sensitization to morphine. In contrast, all amphetamine pretreatment regimens induced sensitization of the locomotor effects of amphetamine (1 mg/kg, i.p.) and pretreatment with morphine (14 x 10 mg/kg, s.c.) induced both short- and long-term sensitization of the locomotor effects of both morphine and amphetamine. These data suggest that the expression of sensitization of the locomotor effects of morphine and amphetamine, at least partially, involves distinct neuroadaptive phenomena.     

GABAA-antagonists and baclofen analgesia

1. Intraperitoneal (i.p.) injection of different doses of baclofen (5, 7.5 and 10 mg/kg) induced analgesia in tail-flick test. The effect was dose-dependent. 2. The antinociception induced by baclofen (10 mg/kg, i.p.) was decreased in animals pretreated with bicuculline (1.5 mg/kg, i.p., 30 min), but not with naloxone (1.5 mg/kg, i.p., 30 min). 3. In picrotoxin (1 mg/kg, i.p., 15 min) pretreated mice, baclofen (5 mg/kg, i.p.) showed a significant analgesic effect. 4. Morphine (6 mg/kg, s.c.) induced analgesia which was antagonized by naloxone pretreatment (1.5 mg/kg, i.p.), while bicuculline or picrotoxin did not alter the morphine response. 5. These data suggest that a part of analgesic effect of baclofen may be mediated through GABAA receptor sites, and differs from that of morphine.     

Effects of glutamate-related drugs on marble-burying behavior in mice: implications for obsessive-compulsive disorder

Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder (OCD). We examined the effects of glutamate-related drugs on marble-burying behavior, which is an animal model of OCD. The uncompetitive N-methyl-d-aspartate (NMDA) antagonists memantine (10 mg/kg, i.p.) and amantadine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity in mice. Similarly, the uncompetitive NMDA receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801, 0.3 mg/kg, i.p.) inhibited marble-burying behavior. However, MK-801 at the same dose markedly increased locomotor activity. By contrast, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and the glutamate release inhibitor riluzole showed no effect on marble-burying behavior and significant suppression of locomotor activity. MK-801 (0.3 mg/kg, i.p.) and memantine (10 mg/kg, i.p.) significantly disrupted prepulse inhibition as an operational measure of sensorimotor gating. By contrast, amantadine (30 mg/kg, i.p.) did not affect prepulse inhibition. These findings suggest that amantadine could be a useful drug for the treatment of OCD.     

Endothelin ETA receptor blockade potentiates morphine analgesia but does not affect gastrointestinal transit in mice

Development of analgesic tolerance and constipation remain a major clinical concern during long-term administration of morphine in pain management. Central endothelin mechanisms are involved in morphine analgesia and tolerance. The present study was conducted to investigate the effect of intracerebroventricular (i.c.v.) and peripheral administration of endothelin ET(A) receptor antagonist, BMS182874, and endothelin ET(B) receptor agonist, IRL1620, on morphine analgesia and changes in gastrointestinal transit in male Swiss Webster mice. Results indicate that morphine (6 mg/kg, s.c.) produced a significant increase in tail flick latency compared to control group. Pretreatment with BMS182874 (50 microg, i.c.v.) significantly enhanced morphine-induced analgesia, while IRL1620 (30 microg, i.c.v.) pretreatment did not affect tail-flick latency values. Changes in gastrointestinal transit were measured by percent of distance traveled by charcoal in the small intestine of gastrointestinal tract. Percent distance traveled in morphine (6 mg/kg, s.c.) treated mice (48.45+/-5.65%) was significantly lower (P<0.05) compared to control group (85.07+/-1.82%). Administration of BMS182874 centrally (50 mug, i.c.v.) or peripherally (10 mg/kg, i.p.) did not affect morphine-induced inhibition of gastrointestinal transit. Pretreatment with IRL1620 (30 microg, i.c.v., or 10 mg/kg, i.v.) also did not affect morphine-induced inhibition of gastrointestinal transit. This study demonstrates that endothelin ET(A) receptor antagonists delivered to the CNS enhance morphine analgesia without affecting gastrointestinal transit.     

Is antagonism of alpha3beta4 nicotinic receptors a strategy to reduce morphine dependence?

18-Methoxycoronaridine, a synthetic iboga alkaloid congener, has been previously shown to attenuate several signs of morphine withdrawal in rats. The recently discovered action of 18-methoxycoronaridine to block alpha3beta4 nicotinic receptors may be responsible for this effect. To test this hypothesis the effects of non-selective alpha3beta4 receptor antagonists, dextromethorphan, mecamylamine, bupropion, and their combinations, were assessed on of acute naltrexone-precipitated (1 mg/kg i.p.) morphine withdrawal in rats. Dextromethorphan (5-40 mg/kg, s.c.), mecamylamine (0.25-4 mg/kg, i.p.) and bupropion (10-30 mg/kg, i.p.) alone produced variable effects on signs of withdrawal. However, two low-dose combinations, i.e., dextromethorphan (5 mg/kg, s.c.) and mecamylamine (0.25 mg/kg, i.p.), mecamylamine (0.25 mg/kg, i.p.) and bupropion (10 mg/kg, i.p.) as well as the three-drug combination significantly attenuated diarrhea and weight loss; none of the agents administered alone had these effects. The results of the present study provide evidence that alpha3beta4 nicotinic receptors are involved in the expression of at least two signs of opioid withdrawal.     

Effect of selective monoamine oxidase inhibitors on the morphine-induced hypothermia in restrained rats

Morphine (30 mg/kg i.p.) produced a hypothermic effect in restrained rats which was antagonized by naloxone pretreatment (10 mg/kg s.c.). This hypothermia was inhibited by deprenyl pretreatment (5 mg/kg i.p.) and by beta-phenylethylamine treatment (25 mg/kg i.p.). However, the effect of morphine was partially potentiated when a higher dose of deprenyl (10 mg/kg i.p.) was administered. Pretreatment with clorgyline (1 mg/kg i.p.) potentiated the morphine-induced hypothermia. In contrast, the effect of morphine was antagonized when a higher dose of clorgyline was used (5 mg/kg i.p.). Based on these results, a possible role of brain serotonin and dopamine in the thermoregulatory effects of morphine is proposed in this paper.