Tail-flick Response Research Articles

D-Pen 2-D-Pen 5]enkephalin, a delta opioid agonist, given intracerebroventricularly in the mouse produces antinociception through mediation of spinal GABA receptors

Intracerebroventricular (ICV) administration of [D-Pen 2-D-Pen 5]enkephalin (DPDPE), a δ opioid receptor agonist, activates a descending antinociceptive pathway that inhibits the tail-flick response in mice. Involvement of spinal GABA receptors in this response was studied by giving GABA antagonists intrathecally. First, antinociception produced by intrathecally administered isoguvacine, a GABA A agonist, was inhibited by intrathecal bicuculline (GABA receptor antagonist) or picrotoxin (chloride channel antagonist). Then, antinoniception induced by ICV DPDPE was antagonized by intrathecal picrotoxin and bicuculline in a dose-and time-dependent manner. Second, intrathecal administration of 2-hydroxysaclofen, a GABA B antagonist (which inhibited antinociception induced by a GABA B, agonist, baclofen, given IT), produced a shift of the dose-response curve for ICV DPDPE to the right. GABA A and B antagonists given together intrathecally produced a greater than additive antagonistic effect against ICV DPDPE-induced antinociception. Thus, the δ agonist action of DPDPE in the brain leads to activation of descending spinal pathways which involve mediation by spinal GABA A and GABA B receptors in the antinociceptive response.

Role of nitric oxide/cyclic GMP in i.c.v. administered beta-endorphin- and (+)-cis-dioxolane-induced antinociception in the mouse.

(+)-cis-Dioxolane (0.5-2 micrograms), a muscarinic receptor agonist, given intracerebroventricularly (i.c.v.) produced a dose-dependent inhibition of the tail-flick response in male ICR mice. (+)-cis-Dioxolane given i.c.v. at a subanalgesic dose (0.25 micrograms), selectively potentiated the antinociceptive response induced by i.c.v. administered beta-endorphin, an epsilon-opioid receptor agonist, but not morphine or [D-Ala2,NMePhe4,Gly5-ol]enkephalin (DAMGO), mu-opioid receptor agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta receptor agonist, or trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methane sulfonate (U50,488H), a kappa-opioid receptor agonist. The antinociceptive response induced by (+)-cis-dioxolane given i.c.v. was attenuated by i.c.v. treatment with N omega-nitro-L-arginine (1 microgram), hemoglobin (120 micrograms) or methylene blue (10 micrograms). The antinociception induced by carbachol given i.c.v. was also antagonized by the i.c.v. treatment with N omega-nitro-L-arginine (1 microgram). However, the same treatment with N omega-nitro-L-arginine, hemoglobin or methylene blue did not affect the beta-endorphin-induced antinociception. The potentiation of beta-endorphin-induced antinociception by (+)-cis-dioxolane was reversed by i.c.v. treatment with N omega-nitro-L-arginine (1 microgram), hemoglobin (120 micrograms) or methylene blue (10 micrograms). On the other hand, the antinociceptive response induced by (+)-cis-dioxolane (1 microgram) given i.c.v. was potentiated by i.c.v. administered L-arginine (20 micrograms) but not D-arginine (20 micrograms). Dibutyryl cyclic GMP at 0.5-2.0 micrograms given i.c.v. produced an antinociceptive response and at subanalgesic dose (0.1 microgram) potentiated i.c.v. beta-endorphin-induced antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemically-diverse ligands at the glycine B site coupled to [formula omitted] (NMDA) receptors selectively block the late phase of formalin-induced pain in mice

The glycine B receptor partial agonists L 687,414, d-cycloserine and (+)-HA 966, and the glycine B receptor antagonists MDL 29,951 and 5,7-dichloro-2,4 dihydroxy-3-phenyl-quinoline dione (DCPQ) dose-dependently inhibited the late phase (LP) of formalin-induced licking (FIL) elicited by intraplantar formalin in mice at doses exerting little motor disruption in the rotarod test. In distinction, the early phase (EP) of FIL and the writhing response to intrabdominal acetic acid were little influenced and, irrespective of stimulus intensity, they failed to modify the tail-flick response to phasic, thermal or mechanical stimulation of the tail. In contrast to glycine B ligands, competitive antagonists at the NMDA receptor recognition site (CPP, CGS 19755, CGP 34879 and 39551) and blockers of the associated ion channel ((+)-MK 801, (−)-MK 801, memantine and ketamine) all blocked both the LP and EP of FIL and induced ataxia at comparable doses. In conclusion, normalization of transmission at NMDA receptors by inhibition of the coupled glycine B site preferentially elicits antinociception against prolonged (chemical) noxious stimulation in the absence of a marked influence upon motor coordination.

The effects of protection by D-Pen 2-D-Pen 5-enkephalin or D-Ala 2-NMePhe 4-Gly-ol-enkephalin against β-chlornaltrexamine in the spinal cord on the antinociception induced by β-endorphin administered intracerebroventricularly in the mouse

Chlornaltrexamine (β-CNA, 0.5 μg) alone or β-CNA plus either μ-agonist, D-Ala 2-NMePhe 4-Gly-ol-enkephalin (DAMGO, 500 ng) or δ-agonist, D-Pen 2-D-Pen 5-enkephalin (DPDPE, 10 μg) was injected intrathecally (i.t.) to protect μ- or δ-opioid receptors, respectively, for 24 h in male ICR mice. The antinociception was assessed by the tail-flick and hot-plate test. DPDPE or DAMGO injected i.t. increased inhibition of the tail-flick and hot-plate response in a dose-dependent manner. The dose-response curve for tail-flick and hot-plate response induced by DPDPE or DAMGO in i.t. saline-treated group significantly shifted to the right in i.t. β-CNA alone treated group but returned to the control level in the group treated with i.t. β-CNA coadministered with DPDPE or DAMGO, respectively. The effects of protection of μ- and δ-opioid receptor in the spinal cord on inhibition of the tail-flick and hot-plate response induced by β-endorphin and morphine administered intracerebroventricularly (i.c.v.) were then studied. Intrathecal pretreatment with β-CNA or β-CNA coadministered with DAMGO attenuated inhibition of the tail-flick response induced by β-endorphin administered i.c.v. However, i.t. treatment with β-CNA coadministered with DPDPE did not affect inhibition of the tail-flick response induced by β-endorphin administered i.c.v. Intrathecal pretreatment with β-CNA or β-CNA coadministered with either DPDPE or DAMGO did not alter inhibition of the hot-plate response induced by β-endorphin administered i.c.v. Intrathecal injection of β-CNA alone did not affect inhibition of the tail-flick and hot-plate response induced by morphine given i.c.v. The results suggest that spinal δ- but not μ-opioid receptors are involved in inhibition of the tail-flick response induced by β-endorphin given i.c.v. On the other hand, inhibition of the tail-flick and hot-plate response induced by morphine given i.c.v. is not mediated through spinal opioid receptors.

Potentiating effect of thyrotropin-releasing hormone and of its synthetic analog digipramine on morphine-induced analgesia

Thyrotropin-releasing hormone (TRH) and its synthetic analog digipramine (DP) shortened the latency of the tail-flick response in mice when injected intraperitoneally in a dose of 5 mg/kg and to potentiate significantly the analgesic action of morphine. Possible mechanisms of these two effects and prospects for their medical use are discussed.

Intrathecal excitatory amino acid (EAA) agonists increase tail flick latencies (TFLs) of spinal rats

The facilitation of spinal nociceptive reflexes that occurs after spinal transection reveals the existence of descending, supraspinally mediated inhibition. Substantial evidence indicates that the excitatory amino acids (EAAs) are involved in these spinal circuits. Therefore, it was hypothesized that reflex facilitation in the spinal animal might be due to the removal of inhibitory input normally exerted on the spinal action of EAAs. If so, the facilitatory decrease in reflex latency, observed in the spinal preparation, might be potentiated by intrathecal (IT) administration of EAA agonists. This was tested by comparing the effect of IT injections of N- methyl- D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) on the thermally elicited tail flick (TF) response of Intact and acute spinal rats. In intact rats, a low (0.25 nM) dose of NMDA produced a hyperalgesic decrease in latency, relative to saline, whereas higher doses produced an overall increase in latency. A large dose (0.5 μM) produced overt signs of toxicity (crippling, self-mutilation, and loss of the reflex). Only the highest (1.0 nM) dose of AMPA affected the response, resulting in a significant increase. After spinal transection, the hyperalgesic reaction to 0.25 nM of NMDA was absent, and latencies were significantly increased by 1.0 nM. The toxic reaction to 0.5 μM appeared to be potentiated. Tail flick responses to AMPA were also significantly increased in spinal rats. Contrary to the prediction, reflex latencies were significantly increased by these drugs after spinal transection. It was suggested that, although the spinal action of EAAs appears to be supraspinally modulated, this influence may be facilitatory rather than inhibitory.

Central delay of the laser-activated rat tail-flick reflex

The latency of the heat-activated rat tail-flick (TF) reflex is dependent upon 4 variables, none of which has previously been determined: activation of cutaneous nociceptors (T N); afferent conduction to the dorsal horn (T A); conduction within the central nervous system (CNS) (central delay); and conduction from the ventral horn (VH) to, and activation of, tail muscles (T E). Using a CO 2 infrared laser (10 W, 45 msec) to produce synchronous activation of tail-skin nociceptors, TF latency (EMG response) was measured in 10 awake rats. Based on shifts in response latency from points of stimulation near the tip and base of the tail, conduction velocity in the afferent limb of the reflex was estimated to be 0.76 ± 0.11 m/sec. This indicates that the response is mediated by C fibers. The rats were then anesthetized with pentobarbital and multiple-unit activity and evoked potentials (EPs) were recorded from the superficial dorsal horn at spinal segments S 3-Co 1 during laser or high-intensity electrical (10 mA, 1 msec) stimulation of the tail. Unit activity and EPs elicited by both stimuli consisted of two distinct components, corresponding to activation of A and C fibers. The difference in latency between laser and electrical evoked activity indicated that 60.00 ± 7.33 msec was required for activation of nociceptors by the laser. Electrical stimulation of the VH at S 3-Co 1 in 3 rats produced a TF (EMG) response in 4 msec. Central delay, calculated as total TF time minus (T N + T A + T E), was 82.3 ± 13.08 msec. This represents the time frame during which modulation of the reflex by an intrinsic, pain-activated, supraspinal system could occur.

Effects of intrathecal or intracerebroventricular pretreatment with pertussis toxin on antinociception induced by beta-endorphin or morphine administered intracerebroventricularly in mice.

We have previously demonstrated that beta-endorphin and morphine, when administered supraspinally, produce antinociception by activating different descending pain inhibitory systems in both rats and mice. However, the signal transduction mechanisms involved in the descending pain-inhibitory systems that are activated by beta-endorphin and morphine administered intracerebroventricularly (i.c.v.) have not been characterized. Therefore, in the present study, the effects of intrathecal (i.t.) and i.c.v. pretreatments with pertussis toxin (PTX) on antinociception induced by beta-endorphin or by morphine administered i.c.v. were studied in ICR mice. Antinociception was assessed by the tail-flick assay and by the hot-plate assay. Intrathecal pretreatment with PTX (0.5 microgram) for 6 days effectively reduced the inhibition of the tail-flick response induced by beta-endorphin (1 microgram) or by morphine (1 microgram) administered i.c.v. However, i.t. pretreatment with PTX was not effective in reducing the inhibition of the hot-plate response induced by beta-endorphin or by morphine administered i.c.v. Intracerebroventricular pretreatment with PTX (0.5 microgram) for 6 days effectively reduced the inhibition of the tail-flick and hot-plate responses induced by morphine (1 microgram), but not that induced by beta-endorphin (1 microgram), administered i.c.v. Our results suggest that there are PTX-sensitive G proteins coupled to the spinal descending pain inhibitory systems that are activated by beta-endorphin and morphine administered i.c.v. At a supraspinal level, i.c.v. morphine- but not beta-endorphin-induced antinociception is mediated by PTX-sensitive G proteins.

Evidence of a role for [formula omitted] (NMDA) receptors in the facilitation of tail withdrawal after spinal transection

Peripheral injury produces a characteristic excitation of spinal cord dorsal horn cells (wind-up) which is associated with a facilitation of spinal nociceptive reflexes (hyperalgesia). These phenomena are believed to be mediated by a trauma-induced increase in the release of excitatory amino acids (EAAs). A similar increase in the activity of dorsal horn neurons and spinal reflexes occurs after spinal transection. Therefore, the present studies examined the possibility that EAAs, acting through the NMDA receptor, might also be involved in behavioral hyperalgesia produced by central injury. The first experiment assessed the effect of pretreatment with the NMDA antagonist, ketamine, on the facilitated tail flick (TF) response of spinally transected rats. Separate groups of animals were spinalized under isoflurane anesthesia alone, intramuscular ketamine anesthesia alone, or a combination of isoflurance and intrathecal ketamine. The TF was examined 24 h later, before and 30 min after an intrathecal injection of morphine. In the second experiment, the effect of intraperitoneal or intrathecal ketamine on the TF was assessed in separate groups of rats that underwent spinal transection or sham surgery under isoflurane anesthesia. Pretreatment with either systemic or intrathecal ketamine did not alter TF facilitation of morphine-induced antinociception in spinal rats. However, both systemic and intrathecal ketamine significantly increased TF latencies in spinal, relative to intact rats. These results indicate that ketamine did not prevent the development of spinal reflex facilitation, but it selectively reduced this reaction once it was established in spinal rats. The data support an involvement of EAAs in reflex facilitation produced by spinal transection.

Differential effects of intrathecally injected galanin on antinociception induced by β-endorphin and morphine administered intracerebroventricularly in mice

The effects of intrathecal (i.t.) and intracerebroventricular (i.c.v.) treatments with galanin on inhibition of the tail-flick and paw-licking hot-plate responses induced by β-endorphin and morphine administered i.c.v. were studied in ICR mice. Galanin (100 ng) given i.t. effectively antagonized inhibition of the tail-flick response induced by i.c.v. administered β-endorphin (1μg) but not morphine (1 μg). However, the same dose of galanin given i.t. did not affect inhibition of the hot-plate response induced by β-endorphin and morphine administered i.c.v. Intrathecal treatment with various doses of galanin (0.1–100 ng) dose-dependently antagonized the inhibition of the tail-flick response induced by β-endorphin administered i.c.v. Galanin (100 ng) in combination with β-endorphin (1 μg) or morphine (1 μg) given i.c.v. did not affect β-endorphin- or morphine-induced inhibition of the tail-flick and hot-plate responses. It is concluded that galanin given i.t. selectively attenuates i.c.v. β-endorphin-induced inhibition of the tail-flick response by inhibiting descending ε-opioid system activated by supraspinally applied β-endorphin.

Antinociceptive effect of l-arginine in diabetic mice

The antinociceptive effect of L-arginine in streptozotocin-indueced diabetic mice was examined. Although s.c. administration of l-arginine produced a dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The antinociceptive effects of l-arginine in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective δ-opioid receptor antagonist. However, neither β-funaltrexamine, a selective μ-opioid receptor antagonist, nor nor-binaltorphimin, a selective κ-opioid receptor antagonist, significantly affected the antinociceptive effect of l-arginine in diabetic and non-diabetic mice. These results suggest that l-arginine produces a marked antinociceptive effect in diabetic mice through the activation of δ-opioid receptors.

Analgesic and Anti-Ulcerogenic Effects of a Polar Extract from Leaves ofVernonia condensata

An aqueous crude extract and a polar fraction derived from this extract were prepared from leaves of Vernonia condensata Baker and assessed in standard rodent models of algesia and ulcerogenesis. Oral pretreatment with the lyophilized crude extract (200 mg/kg) significantly reduced mouse writhing counts caused by the i.p. injection of increasing concentrations (0.6-1.2%) of acetic acid (0.1 ml/10 g). In doses ranging from 50 to 400 mg/kg, the crude extract inhibited dose-dependently mouse writhing induced by acetic acid (0.6%) (ED50 = 241 mg/kg) and also markedly increased the sleeping time induced by thiopental. The polar fraction, prepared by washing out the crude extract with chloroform, did not alter sleeping time but kept the analgesic activity (ED50 = 154 mg/kg), indicating that these effects are indeed dissociated. In contrast, the tail flick response in the immersion test was not modified by the crude extract or the polar fraction. The relative potency with which polar fraction and non-steroidal anti-inflammatory drugs inhibited mouse writhing caused by acetic acid in mice was indomethacin >> dypirone > polar fraction > aspirin. Furthermore, the combined polar fraction/aspirin or polar fraction/indomethacin treatments presented a marked synergistic effect, in contrast to what was observed when submaximal doses of indomethacin and aspirin were coadministered, suggesting that polar fraction and aspirin like drugs may have complementary analgesic actions. Finally, despite being able to potentiate the analgesic effect of indomethacin in mouse writhing caused by acetic acid, the pretreatment with the polar fraction (200 mg/kg, oral) significantly prevented indomethacin-induced ulcers in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral studies on LEK-8804, a new ergoline derivative with potent 5-HT 1A receptor agonist and 5-HT 2 receptor antagonist activity

The 5-HT 1A receptor-mediated tail flick response in rats and the 5-HT 2 receptor-mediated head twitch response in mice were used to study the functional activity of a new ergoline derivative, 9,10-didehydro- N-(2-propynyl)-6-methylergoline-8β-carboxamide (LEK-8804). LEK-8804 dose-dependently elicited spontaneous tail flicks in rats, indicating a full 5-hydroxytryptamine 1A (5-HT 1A) agonist activity. This effect was very similar to that produced by the selective 5-HT 1A agonist 8-OH-DPAT, both in terms of potency and time-effect relationship, and was blocked by the selective 5-HT 1A antagonist NAN-190. In contrast, LEK-8804 by itself failed to produce head twitches in mice but dose-dependently inhibited the 5-hydroxytryptophan (5-HTP)-induced behavior. The inhibitory effect of LEK-8804 upon 5-HTP-induced head twitches was not attenuated by the selective 5-HT 1A antagonist NAN-190. This indicates that probably not the agonist action on 5-HT 1A receptors but instead the antagonism on 5-HT 2 receptors was involved in the inhibition of head twitch response. It is suggested that LEK-8804 is a potent full 5-HT 1A receptor agonist with possible 5-HT 2 receptor antagonist properties.

Antinociception without motor blockade after subarachnoid administration of S-(+)-ibuprofen in rats

This study was designed to determine whether the nonsteroidal anti-inflammatory drug (NSAID) sodium S-(+)-ibuprofen (IB), can be used intrathecally as a substitute analgesic for opiates to avoid the side effects of intrathecal narcotics. One week or more after surgical implantation of subarachnoid catheters, four groups of Sprague-Dawley rats were given 0.05 ml subarachnoid injections containing one of the following: Group A, normal saline (NS); Group B, IB 0.25 mg, 0.5 mg and 1.5 mg; Group C, morphine (M)_0.05 mg and 0.025 mg; Group D received NS or IB 1.5 mg. Animals were sacrificed for spinal cord examination one week after injection. Tail flick response latency (TFL) was determined before and 15, 30, 60, 120 and 180 minutes after each injection. TFL differences were compared. IB 1.5 mg vs NS, IB 0.5 mg vs NS, IB 0.25 mg vs M 0.05 mg, IB 0.25 mg vs M 0.025 mg, M 0.05 mg vs NS, and M 0.025 vs NS showed p <0.05. IB 1.5 mg vs M 0.05 mg and M 0.025 mg, IB 0.5 mg vs M 0.05 mg and M 0.025 mg revealed no significant difference. No motor impairment was observed in any animal. Light microscopy of the spinal cord revealed no evidence of pathological changes in any animal (group D).

Regulation by lithium of the antagonistic effect of cholecystokinin octapeptide on ohmefentanyl-induced antinociception

The antagonistic effect on opioid analgesia of central cholecystokinin octapeptide (CCK-8) has been amply demonstrated by behavioral and electrophysiological studies, although the mechanisms of action remain obscure. Since the phosphatidylinositol (PI) system is known to be involved in CCK effects in pancreatic tissue, and lithium has been shown to interfere with PI turnover, we sought to investigate whether LiCl would block the antiopioid effect of CCK-8 in the CNS. Nociceptive thresholds were assessed by the latency of the tail flick response (TFL). Intrathecal injection (ith) of LiCl at 4 cumulative doses (1.25–25 μmol) produced no significant change in the baseline TFL, nor was the antinociceptive effect induced by ohmefentanyl (OMF, the μ -selective opioid agonist, 20 ng, ith) reversed by LiCl. However, OMF-induced antinociception was dose-dependently reversed by CCK-8 (1–16 ng, ith), which alone at 5 cumulative doses (1–20 ng) had no influence on TFL, and the reversal effect of CCK-8 could be readily antagonized by LiCl (0.6–20 μmol, ith). The results are interpreted to mean that the PI signal system may play an important role in mediating the antiopioid effect of CCK-8.

Antinociceptive effect of brain-derived neurotrophic factor and neurotrophin-3

Infusions of brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), but not nerve-growth factor, into the rat midbrain significantly elevated the tail-flick response latency. Analgesia was observed as soon as 24 h after the onset of infusion, reached maximum levels by day 5 and remained constant for a least an additional 6 days, suggesting no development of tolerance. BDNF infusion also increased latency in the hot-plate test. Naloxone administration reversed the BDNF-induced increase in the tail-flick latency. The antinociceptive effect of BDNF infusion was accompanied by an augmentation in serotonergic activity within the brain and spinal cord. These data demonstrate both an effedt of BDNF and NT-3 on serotonergic neurons and an analgesic property of these neurotrophins which appears to involve both serotonin and opioid mechanisms.

The NMDA Receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro- l-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids

Once daily s.c. administration of 5 mg/kg morphine, a mu-opioid agonist, or U50488H (U50), a kappa 1-opioid agonist, for 5 days in male CD-1 mice results in a 2–3-fold shift to the right of the respective analgesic (tail flick) dose-response curves, indicating the development of tolerance. Concurrent s.c. administration of the competitive NMDA receptor antagonist, LY274614 (LY), at 24 mg/kg/24 h infusion (osmotic pump) or 6 mg/kg i.p. once daily attenuates the development of morphine tolerance, when the response to saline plus morphine is compared on day 5 with LY plus morphine. Using this paradigm, once daily administration of either the non-competitive NMDA antagonist, MK-801, at 0.3 mg/kg i.p. or the nitric oxide synthase inhibitor, NG-nitro- l-arginine (NorArg), at 1 mg/kg i.p. twice daily attenuated the development of morphine tolerance. None of these drugs modify the tail-flick response or alter the ED 50 for morphine. In contrast, co-administration of LY, MK-801 or NorArg, as above, failed to attenuate the development of tolerance to U50 or to the kappa 3-opioid agonist, naloxone benzoylhydrazone (NalBzoH). These results suggest that mu-opioid tolerance but not kappa 1- or kappa 3-opioid tolerance involves the mediation of NMDA receptors and the nitric oxide system.

Supraspinal delta receptor subtype activity of heroin and 6-monoacetylmorphine in Swiss webster mice

The purpose of this study was to determine which delta (δ) opioid receptor subtype, δ 1 or δ 2, was involved in producing the antinociceptive action of heroin and 6-monacetylmorphine (MAM) in Swiss Webster mice. Previous work from this laboratory established that heroin and MAM, given intracerebroventricularly (i.c.v.) in Swiss Webster mice, produce antinociception through activation of supraspinal δ receptors. Naltrindole, but not naloxone or nor-binaltorphimine, antagonizes the inhibitory action of heroin and MAM in the tail-flick test. Recent literature documents the occurence of subtypes of the δ opioid receptor and the availability of selective antagonists. 7-Benzylidenenaltrexone (BNTX) antagonizes the antinociception induced by δ 1 receptor agonists without affectingthat induced by δ 2 receptor agonists. Naltriben (NTB) selectively inhibits δ 2- but not δ 1-induced antinociception. In the present study BNTX and NTB were administered i.c.v. with heroin and MAM to determine the δ receptor subtype responsible for inhibition of the tail-flick response in Swiss Webster mice. The ED 50 for heroin-induced antinociception was increased 19-fold by BNTX and was not altered by NTB administration. On the other hand, the ED 50 value of MAM was increased 3-fold by NTB and was not altered b by BNTX administration. These results suggest that heroin activated supraspinal δ 1 receptors and MAM acted on supraspinal δ 2 receptors to produce antinociception in Swiss Webster mice.

O-392 - Antinociceptive effect of L-arginine in diabetic mice.

Abstract The antinociceptive effect of L -arginine in streptozotocin-indueced diabetic mice was examined. Although s.c. administration of l -arginine produced a dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The antinociceptive effects of l -arginine in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective δ-opioid receptor antagonist. However, neither β-funaltrexamine, a selective μ-opioid receptor antagonist, nor nor-binaltorphimin, a selective κ-opioid receptor antagonist, significantly affected the antinociceptive effect of l -arginine in diabetic and non-diabetic mice. These results suggest that l -arginine produces a marked antinociceptive effect in diabetic mice through the activation of δ-opioid receptors.

Antinociceptive effect of lipopolysaccharide from Pantoea agglomerans on streptozotocin-induced diabetic mice

The antinociceptive effect of lipopolysaccharide from Pantoea agglomerans (LPSp) in streptozotocin-induced diabetic mice was examined. Although subcutaneous (s.c.) administration of LPSp produced a dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The antinociceptive effects of LPSp in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective δ-opioid receptor antagonist or nor-binaltorphimine, a selective κ-opioid receptor antagonist, but not by β-funaltrexamine, a selective μ-opioid receptor antagonist. These results suggest that LPSp produces a marked antinociceptive effect in diabetic mice through the activation of δ- and κ-opioid receptors.