Involvement of dynorphin in immobilization stress-induced antinociception in the mouse.

The effect of antiserum against [Met(5)]-enkephalin, [Leu(5)]-enkephalin, beta-endorphin, or dynorphin A-(1-13) administered intracerebroventricularly (i.c.v.) or intrathecally (i. t.) on immobilization-induced antinociception was studied in ICR mice. Antinociception was assessed by the tail-flick assay. Immobilization of the mouse increased inhibition of the tail-flick response at least 1 h. The i.c.v. or i.t. injection with antiserum against dynorphin A-(1-13) at the dose of 200 microg significantly attenuated immobilization-induced inhibition of the tail-flick response. However, antiserum against [Met(5)]-enkephalin, [Leu(5)]-enkephalin, or beta-endorphin did not affect the immobilization stress-induced antinociception. Furthermore, i.c.v. or i.t. injection with nor-binaltorphimine (Nor-BNI; from 1 to 20 microg) effectively inhibited immobilization stress-induced inhibition of the tail-flick response in a dose-dependent manner. However, beta-FNA (from 0.5 to 2 microg) or naltrindole (from 1 to 20 microg) administered i.c.v. or i.t. did not affect immobilization stress-induced antinociception. Our results suggest that supraspinally and spinally located dynorphin appears to be involved in the production of immobilization stress-induced antinociception via stimulating kappa-opioid receptors.     

Alpha-adrenoceptor involvement in swim stress-induced antinociception in the mouse

Three different intensities of swim stress produced stress-induced antinociception (SIA) in mice which was assessed either by the reduction in the number of abdominal constrictions produced by acetic acid or by an increase in reaction time on a hot-plate. The involvement of alpha-adrenoceptors in the three models of SIA was investigated using selective antagonists. SIA produced by the mild stress of a 30 s warm water swim was attenuated by idazoxan (0.5-1 mg kg-1), and by yohimbine at a dose (1 mg kg-1) which reduced antinociception produced by clonidine (12.5-50 micrograms kg-1). Indoramin (1-2 mg kg-1) did not affect this model of SIA, but reversed phenylephrine induced inhibition of the constrictions. A 3 min room temperature swim increased reaction times on the hot-plate and this naloxone-sensitive SIA was reduced significantly by prazosin (1-2 mg kg-1), idazoxan (0.5-1 mg kg-1) and yohimbine (0.5-1 mg kg-1) but enhanced by clonidine (0.5 mg kg-1) and noradrenaline (NA) (10 micrograms i.c.v.). Mice treated with 6-hydroxydopamine (60 + 60 micrograms i.c.v.) were hypersensitive to the hot-plate and did not develop SIA. Levels of noradrenaline in the brain (minus the cerebellum) were decreased after the room temperature swim SIA. The most severe stress of a cold water swim produced SIA on the hot-plate which was initially naloxone-insensitive.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of histamine in naloxone-resistant and naloxone-sensitive models of swim stress-induced antinociception in the mouse

The antinociceptive activity of histamine in male mice has been demonstrated using chemical and thermal noxious stimuli and its involvement in naloxone-sensitive and naloxone-insensitive models of stress-induced antinociception investigated. In the abdominal constriction test, histamine and dimaprit but not histidine, induced antinociception. Compound 48/80 and H1 antagonists (diphenhydramine, mepyramine and promethazine) and large doses of H2 antagonists (cimetidine and zolantidine) produced antinociception in this test. Antinociception induced by histamine was refractory to mepyramine, metiamide and naloxone. Histamine and non-antinociceptive doses of its antagonists had no influence on the naloxone-resistant warm water swim stress-induced antinociception. In the hot-plate test, histamine agonists, except the H3 agonist (R) alpha-methyl histamine (alpha-MeHA), were antinociceptive but all these agents augmented the naloxone-sensitive room temperature swim stress-induced antinociception, after either intraperitoneal or intraventricular injection. The antinociceptive action of dimaprit was not antagonized by zolantidine which, like other histamine antagonists excluding metiamide, also produced antinociception and enhanced room temperature swim stress-induced antinociception. These findings suggest that histamine is involved in pathways mediating antinociception in the mouse and that such pathways are activated in a naloxone-sensitive model of stress-induced antinociception but not in a naloxone-insensitive model.     

Socio-psychological stress-induced antinociception in diabetic mice

Rationale: Although it is well established that different forms of stress produce a pronounced antinociception, the effect of diabetes on psychological stress-induced antinociception is not yet clear. Objectives: The effect of diabetes on psychological stress-induced antinociceptive effect was assessed in mice. Methods: Animals were rendered diabetic by an injection of streptozotocin (200 mg/kg, IV). Mice were exposed to psychological stress in the compartment of a communication box. The antinociceptive response was evaluated by the tail-flick test, using radiant heat as a stimulus, which was performed before stress (pre-stress latency) and 0, 30 and 60 min after stress. Results: Exposure to socio-psychological stress for 5, 10 and 15 min produced duration-dependent antinociception in diabetic mice. However, in non-diabetic mice, no appreciable antinociception was found even in the case of socio-psychological stress for 15 min. Pretreatment with diazepam (0.3 mg/kg, IP) significantly attenuated socio-psychological stress-induced antinociception in diabetic mice (vehicle: 62.9±5.5%, n=10; diazepam: 22±1%, n=10). Furthermore, pretreatment with flumazenil (1 mg/kg, IV), a benzodiazepine receptor antagonist, also significantly reduced socio-psychological stress-induced antinociception in diabetic mice (vehicle: 77.9±5.0%, n=10; flumazenil: 5.8±1.2%, n=10). In contrast, pretreatment with methyl β-carboline-3-carboxylate (β-CCM, 2 mg/kg, IV), a benzodiazepine receptor inverse agonist, significantly enhanced socio-psychological stress-induced antinociception in non-diabetic mice (vehicle: 4.9±0.6%, n=10; β-CCM: 61.5±5.9%, n=10), but not in diabetic mice (vehicle: 50.7±4.5%, n=10; β-CCM: 64.4±7.2%, n=10). Conclusions: These results indicate that emotional stress can readily induce antinociception in diabetic mice. Furthermore, this enhanced emotional stress-induced antinociception might be attributable to an increase in the production and/or release of endogenous ligands for benzodiazepine receptors, such as diazepam binding inhibitor, which act as inverse benzodiazepine receptor agonists. Received: 1 September 1999 / Final version: 12 January 2000     

Immobilisation stress-induced antinociception in rats: possible role of serotonin and prostaglandins.

Immobilisation of rats for 1, 2 and 4 h induced duration-related antinociception. Antinociception induced by 4 h immobilisation was significantly inhibited after pretreatment by drugs known to inhibit synthesis of serotonin, induce degeneration of serotonergic neurones and inhibit prostaglandin synthesis. The results indicate that immobilisation stress induces autoanalgesia, which may be dependent on the availability of endogenous serotonin and prostaglandins in rat brain.     

Characterization of socio-psychological stress-induced antinociception in the formalin test in mice

The antinociceptive effect induced by exposure to socio-psychological (PSY) stress using a communication box was assessed by the formalin test in mice, compared with those by exposure to footshock (FS) stress and forced swimming (SW) stress. After the termination of stress exposure, whereas exposure to FS- and SW-stress resulted in the attenuation of the formalin-induced biphasic pain response over 15 min, no appreciable antinociceptive effect was found in the case of PSY stress. When exposure to PSY stress was started during the period of early or late phase of pain after the formalin injection, the antinociceptive effect was maintained for 5-15 min; however, further exposure to PSY stress was not effective for producing antinociception. In the tail-pinch test, likewise, exposure to PSY stress longer than 5 min rather decreased the intensity of antinociception. We conclude that PSY stress in this tonic pain paradigm produces antinociception, but further continuous exposure to the emotional stress caused mice to become recuperative even in such a fear-inducing situation.     

Effects of spinally and supraspinally injected 3-isobutyl-1-methylxanthine, cholera toxin, and pertussis toxin on immobilization stress-induced antinociception in the mouse.

The effects of intracerebroventricular (i.c.v.) and intrathecal (i.t.) 3-isobutyl-1-methylxanthine (IBMX), cholera toxin (CTX) and pertussis toxin (PTX) administration on immobilization-induced antinociception were studied in ICR mice. Antinociception was assessed by the tail-flick assay. Immobilization of the mouse increased inhibition of the tail-flick response for at least 1 h. The pretreatment with i.t. IBMX (0.01-1 ng), but not i.c.v. IBMX, significantly attenuated immobilization-induced inhibition of the tail-flick response. The pretreatments with i.c.v. PTX (0.05-0.5 microg) as well as i.t. CTX, but neither i.c.v. CTX (0.05-0.5 microg) nor i.t. PTX, potentiated the inhibition of the tail-flick response induced by immobilization stress. Our results suggest that spinally located phosphodiesterase appears to be involved in the production of immobilization stress-induced antinociception. In addition, inactivation of supraspinally located PTX-sensitive G-proteins and spinally located CTX-sensitive G-proteins may modulate immobilization stress-induced antinociception.     

Saccharin effects on morphine-induced antinociception in the mouse formalin test.

This study was performed to investigate the role of sweetness and taste sensations of the non-caloric sweetener saccharin on pain and morphine antinociception by the formalin test in mice. The formalin test was chosen because it measures the response to a long-lasting nociceptive stimulus and thus may closely resemble clinical pain. The total time (seconds) spent licking and biting the injected paw (indices of nociception) during periods of 0-5 min (early phase) and 10-30 min (late phase) were measured as an indicator of pain and inflammatory responses. A 12 days pretreatment of animals with saccharin (0.04%, 0.08%, 0.16%) produced complex effects on the action of morphine. All doses significantly potentiated the low dose (1.5 mgkg(-1)) of morphine-induced analgesia in the early phase significantly but antagonized the effect of morphine (3 mgkg(-1)). The effect of high doses of morphine (6-9 mgkg(-1)) was antagonized by the low dose of saccharin (0.04%), but the effect of morphine (6 mgkg(-1)) was potentiated with high concentrations of saccharin (0.08% and 0.16%). All doses of saccharin decreased the analgesic effect of morphine at a dose of 9 mgkg(-1). Analgesic effects of low doses of morphine (1.5-3 mgkg(-1)) were decreased by all doses of saccharin in the late phase. Different concentrations of saccharin also affected the antagonistic effect of naloxone (0.4 mgkg(-1)) on morphine-induced analgesia in both phases of the formalin test. The high dose of saccharin (0.16%) potentiated the effect of naloxone in the late phase. The results obtained suggest that sweet sensation is an important factor in mediating morphine analgesic properties. It is therefore inappropriate to use different concentrations of sweet saccharin solutions interchangeably.     

The role of neurotransmitters in stress-induced antinociception (SIA)

The role of the neurotransmitters, norepinephrine, dopamine and serotonin in stress-induced antinociception (SIA) was examined by altering neurochemical tone with appropriate pharmacological tools. Quipazine (15.0 mg/kg, IP) a serotonin agonist, increased the peak and duration of antinociception following stress and BC-105 (3.0 mg/kg, IP), a serotonin antagonist, blocked the increase of tail-flick latency following stress. Clonidine (0.1 mg/kg, SC) an alpha 2 agonist, markedly decreased SIA whereas phenoxybenzamine (2.5 mg/kg, IP), an alpha 1 antagonist, increased the peak and duration of SIA. When dopaminergic tone was increased with apomorphine (0.05 mg/kg, SC) the increase of tail-flick latency after stress was markedly attenuated whereas blockage of dopamine receptors with haloperidol (2.5 mg/kg, IP) increased the peak and duration of SIA. Alterations of serotonergic, but not noradrenergic or dopaminergic, tone had similar effects on increased latency in tail-flick test produced by brain stimulation produced analgesia (SPA), morphine and SIA. These data support the hypothesis that alterations in tail-flick latency involves a serotonergic system.     

Perinatal lead exposure impairs opioid but not non-opioid stress-induced antinociception in developing rats.

1. The development of opioid systems has been shown to be sensitive to perinatal exposure to lead. We have studied the effects of such exposure on opioid and non-opioid mediated stress-induced antinociception in developing rats. 2. Lead was administered in the maternal drinking water from conception to postnatal day 14 at 300 and 1000 p.p.m. Twenty and 25 day old rats were subjected to swimming stress and antinociception measured using the tail immersion test. 3. A 3 min swim-stress induced an opioid-mediated antinociceptive response in 20 day old rats which was attenuated by 300 p.p.m. lead and by 1000 p.p.m. lead treatment in a dose-related manner. A 10 min swim-stress induced a non-opioid mediated antinociceptive response in 25 day old rats which was not antagonised by 300 or 1000 p.p.m. lead. 4. Naloxone antagonised the residual antinociception observed in 20 day old animals treated with 300 p.p.m. lead and had no effect on antinociception in control or lead-treated 25 day old rats. 5. Using a lead exposure model considered to represent subclinical lead toxicity in man, it was shown that perinatal lead exposure disrupts opioid but not non-opioid mediated stress antinociception.     

Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia

Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB(1) antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Delta(9)-tetrahydrocannabinol (Delta(9)-THC). The converse was also true; acute Delta(9)-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Delta(9)-THC. Repeated exposure to footshock (3 min/day for 15 days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans.     

Sex difference in naloxone antagonism of swim stress-induced antinociception in mice

A 30 sec swim in water at 30 degrees C reduced the number of abdominal constrictions produced in mice by the intraperitoneal injection of acetic acid. In male mice this reduction in abdominal constrictions induced by swim stress was not affected by prior subcutaneous administration of naloxone hydrochloride. However, in the female mice naloxone hydrochloride administered 5 min, 10 min, or 15 min before the 30 sec swim dose-dependently antagonized the effect of swim stress on the abdominal constriction response to i.p. acetic acid. In view of the possibility that female mice may perceive the stress at different intensity from those of the male, the effects of different swimming durations on female mice were also studied. It was found that a 15 sec swim in water at 30 degrees C was sufficient to induce antinociceptive response to i.p. acetic acid. The antinociceptive effect was greater if the duration of swim was extended to 60 sec. In both instances, prior administration of naloxone dose-dependently reduced the antinociceptive effect induced by swimming. These results suggest sex difference in the involvement of endogenous opioid system in swim stress-induced antinociception in mice.     

Modulation of morphine antinociception in the mouse by endogenous nitric oxide.

1. L-Arginine (100-1000 mg kg-1) administered orally (p.o.) or intraperitoneally (i.p.), but not intracerebroventricularly (i.c.v., 0.08 mg per mouse), reduced the antinociceptive effect of morphine (0.5-10 mg kg-1 s.c.) assessed in mice using three different tests: hot plate, tail-flick and acetic acid-induced writhing. D-Arginine (up to 1000 mg kg-1 p.o. or i.p.) was ineffective. 2. NG-Monomethyl-L-arginine (L-NMMA, 5-50 mg kg-1 i.p.) and NG-nitro-L-arginine methyl ester (L-NAME, 5- 30 mg kg-1 i.p.), but not NG-nitro-D-arginine methyl ester (D-NAME, 30 mg kg-1 i.p.), reversed in all assays the effect of L-arginine on morphine-induced antinociception. 3. Morphine (10 mg kg-1 s.c.), L-arginine (1000 mg kg-1 p.o.) or L-NAME (30 mg kg-1 i.p.), either alone or in combination, did not produce changes in locomotor activity or sensorimotor performance of animals. 4. These results suggest that the L-arginine-nitric oxide pathway plays a modulating role in the morphine-sensitive nociceptive processes.     

Effect of delayed weaning on opioid receptor control of swim stress-induced antinociception in the developing rat.

1. The opioid type of swim-stress induced antinociception (SIA) is mediated via mu-sites in preweanling rats and predominantly by delta-sites in postweanling animals. We have studied the effect of delay of weaning on the receptor transition of this behaviour in the developing rat. 2. Litters were weaned normally at day 21 or allowed to remain with their mothers until assessment of swim SIA. Animals were stressed by warm water (20 degrees C) swimming for 3 min periods and antinociception assessed by the tail immersion test (50 degrees C). 3. Naloxone (10 mg kg-1) partially reversed swim SIA in both 25 day old weaned and non-weaned rats. 4. Naltrindole (1 mg kg-1) partially reversed swim SIA in 25 day old weaned rats but had no effect in non-weaned animals. Naltrindole (5 mg kg-1) completely abolished swim SIA in weaned rats but was without effect in non-weaned groups. Antinociceptive responses to the mu-agonist, alfentanil (60 micrograms kg-1) were unaffected by naltrindole at 1 mg kg-1 but were partially reversed at 5 mg kg-1. 5. In 30 day old non-weaned rats, naltrindole (5 mg kg-1) abolished the swim SIA. 6. In conclusion, transition from mu to delta-receptor control of swim SIA in rat pups can be delayed by between 5 and 10 days by delay of weaning. The environmental stimulus of weaning can activate opioid receptor subtype operation of biological responses in the developing animal.     

Effects of spinally and supraspinally injected 3-isobutyl1-methylxanthine,cholera toxin,and pertussis toxin on cold water swimming stress-induced antinociception in the mouse

• 1.1. The cold (4°C) water swimming stress (CWSS) for 3 min significantly increased the inhibition of the tail-flick response in ICR mice.
• 2.2. Pertussis toxin (PTX, 0.05–0.5 μg) in mice pretreated intrathecally (IT) for 6 days attenuated the inhibition of the tail-flick response induced by CWSS. However, intracerebroventricular (ICV) pretreatment with PTX at the same doses did not affect CWSS-induced inhibition of the tail-flick inhibition.
• 3.3. 3-Isobutyl-l-methylxanthine (IBMX, 0.01–1 ng) in mice pretreated IT for 10 min dose-dependently attenuated the inhibition of the tail-flick response induced by CWSS. However, IBMX in mice ICV pretreated ICV at the same doses was not effective in attenuating the CWSS-induced inhibition of the tail-flick response.
• 4.4. Neither IT nor ICV pretreatment with cholera toxin (CTX, 0.05–0.5 μg) for 24 hr affected the inhibition of the tail-flick response induced by CWSS.
• 5.5. The ICV or IT injection of PTX, CTX, or IBMX did not affect the basal tail-flick response latency.
• 6.6. It is concluded that spinal, but not supraspinal, PTX-sensitive G-proteins and cAMP phosphodiesterase may be involved in the antinociception produced by CWSS. However, neither spinal nor supraspinal CTX-sensitive G-proteins appear to be involved in mediating the antinociception induced by CWSS.

     

Role of protein kinase C in desensitization of spinal delta-opioid-mediated antinociception in the mouse.

1. Receptor phosphorylation and down-regulation by protein kinases may be a key event initiating desensitization. The present studies were designed to investigate the effect of a potent protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu), on antinociception induced by intrathecal (i.t.) administration of a selective delta-opioid receptor agonist [D-Ala2] deltorphin II in the male ICR mouse and on the specific binding of [3H]-[D-Ser2, Leu5]enkephalin-Thr6 (DSLET), a delta-opioid receptor ligand, in the crude synaptic membrane of the spinal cord. 2. Intrathecal (i.t.) pretreatment with PDBu at low doses, which injected alone did not affect the basal tail-flick latency, dose-dependently attenuated the antinociception induced by i.t. administration of [D-Ala2]deltorphin II. The attenuation of i.t.-administered [D-Ala2] deltorphin II-induced antinociception by PDBu was reversed in a dose-dependent manner by i.t. concomitant pretreatment with a specific PKC inhibitor, calphostin C. 3. In the binding experiment, incubation of the crude synaptic membrane of the spinal cord for 2 h at 25 degrees C with PDBu (0.03 to 10 microM) caused a dose-dependent inhibition of the [3H]-DSLET binding. Scatchard analysis of [3H]-DSLET binding revealed that PDBu at 10 microM displayed a 30.7% reduction in the number of [3H]-DSLET binding sites with no significant change in affinity, compared with the non-treatment control, indicating that the activation of membrane-bound PKC by PDBu causes a decrease in the number of specific delta-opioid agonist binding sites. 4. An i.t. injection of [D-Ala2]deltorphin II produced an acute antinociceptive tolerance to the antinociceptive effect of a subsequent i.t. challenge of [D-Ala2]deltorphin II. Concomitant pretreatment with calphostin C markedly prevented the development of acute tolerance to the i.t.-administered [D-Ala2]deltorphin II-induced antinociception. On the other hand, a highly selective protein kinase A (PKA) inhibitor, KT5720, did not have any effect on the development of acute tolerance to [D-Ala2]deltorphin II antinociception. 5. These findings suggest that a loss of specific delta-agonist binding by the activation of PKC by PDBu is involved in the PDBu-induced antinociceptive unresponsiveness to delta-opioid receptor agonist in the mouse spinal cord. Based on the acute tolerance studies, we propose that PKC, but not PKA, plays an important role in the process of homologous desensitization of the spinal delta-opioid receptor-mediated antinociception.     

Pentobarbital attenuates antinociception induced by i.c.v. morphine but not beta-endorphin in the mouse.

The effects of pentobarbital anesthesia (45 mg/kg i.p.) on the inhibition of the tail-flick response induced by beta-endorphin and morphine injected intracerebroventricularly (i.c.v.) and intrathecally (i.t.) were studied in male ICR mice. Pentobarbital anesthesia attenuated the inhibition of the tail-flick response induced by morphine but not beta-endorphin given i.c.v. However, the tail-flick inhibition induced by morphine given i.t. was not attenuated by pentobarbital. beta-Endorphin-(1-27) (3 micrograms) given i.c.v. or naloxone (2 micrograms) given i.t. blocked inhibition of the tail-flick response induced by morphine given i.c.v. only in pentobarbital-anesthetized mice but not in conscious mice. beta-Funaltrexamine (beta-FNA, 2.5 micrograms) given i.c.v. or yohimbine (2 micrograms) and methysergide (2 micrograms) injected i.t. blocked the morphine (i.c.v.)-induced inhibition of the tail-flick response in conscious mice but not in pentobarbital-anesthetized mice. The results indicate that pentobarbital attenuates the morphine-induced inhibition of the tail-flick response by inhibiting descending noradrenergic and serotonergic pathways and uncovers a descending opioid system. The tail-flick inhibition induced by supraspinal morphine is mediated by stimulation of mu-opioid receptors in conscious mice and epsilon-opioid receptors in pentobarbital-anesthetized mice. The epsilon-opioid receptor-mediated descending system activated by supraspinally injected beta-endorphin is not attenuated by pentobarbital anesthesia.     

Involvement of spinal delta 1-opioid receptors in forced walking stress-induced antinociception in the tail-flick test in mice

The purpose of this study was to elucidate the involvement of spinal delta-opioid receptor subtypes in forced walking stress-induced antinociception mice. We first confirmed that forced walking stress produced walking duration-dependent antinociception in mice as determined by the tail-flick test. Intrathecal treatment with 7-benzylidenenaltrexone, a selective delta 1-opioid receptor antagonist, significantly attenuated forced walking stress-induced antinociception. In contrast, intrathecal treatment with naltriben, a selective delta 2-opioid receptor antagonist, had no significant effect on forced walking stress-induced antinociception. Intracerebroventricular treatment with either 7-benzylidenenaltrexone or naltriben had no effect on the forced walking stress-induced antinociception. These results suggest that forced walking stress-induced antinociception is mediated by spinal delta 1-opioid receptors in mice.     

Increase of nitric oxide production by L-arginine potentiates i.c.v. administered beta-endorphin-induced antinociception in the mouse.

Pretreatment (i.c.v.) of mice with L-arginine but not D-arginine potentiated beta-endorphin-induced (i.c.v. administered) inhibition of the tail-flick response. The potentiation was attenuated by N omega-nitro-L-arginine methyl ester, a selective inhibitor of nitric oxide synthase. This observation suggests that increased production of nitric oxide from L-arginine mediates the potentiation of beta-endorphin-induced antinociception.