naltrindole and Pain

The development of σ

Topics: Animals; Guinea Pigs; Hydrogen; Hydrogen Sulfide; Ligands; Male; Morpholines; Pain; Piperazines; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor

Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective μ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced β-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for μ- and δ-opioid receptors and for the endogenous opioid β-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.

Topics: Analgesics; Animals; Cinnamates; Dinoprostone; Ketamine; Male; Mice; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu

In the present study, we characterize the antinociceptive effects produced by the chemokine CCL4 in mice. The intraplantar administration of very low doses of CCL4 (0.1-3 pg) produced bilateral antinociception assessed by the unilateral hot-plate test (UHP) without evoking chemotactic responses at the injection site. Moreover, the subcutaneous administration of CCL4 (3-100 pg/kg) also yielded bilateral antinociception in the UHP and the paw pressure test and reduced the number of spinal neurons that express Fos protein in response to noxious stimulation. The implication of peripheral CCR5 but not CCR1 in CCL4-evoked antinociception was deduced from the inhibition produced by systemic but not intrathecal, administration of the CCR5 antagonist DAPTA, and the inefficacy of the CCR1 antagonist J113863. Besides, the inhibition observed after subcutaneous but not intrathecal administration of naloxone demonstrated the involvement of peripheral opioids and the efficacy of naltrindole but not cyprodime or nor-binaltorphimine supported the participation of δ-opioid receptors. In accordance, plasma levels of met-enkephalin, but not β-endorphin, were augmented in response to CCL4. Likewise, CCL4-evoked antinociception was blocked by the administration of an anti-met-enk antibody. Leukocyte depletion experiments performed with cyclophosphamide, anti-Ly6G, or anti-CD3 antibodies indicated that the antinociceptive effect evoked by CCL4 depends on circulating T lymphocytes. Double immunofluorescence experiments showed a four times more frequent expression of met-enk in CD4

Topics: Analgesics; Animals; CD4-Positive T-Lymphocytes; Chemokine CCL4; Enkephalin, Methionine; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Nociception; Pain; Pain Measurement

Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined.. The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE. The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 μg), naltrindole (60 μg) and nor-binaltorfimina (200 μg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 μg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng).. These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes.

Topics: Analgesics; Animals; Cinnamates; Dinoprostone; Disease Models, Animal; Male; Mice; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Opioid Peptides; Pain; Receptors, Opioid; Serotonin

This study was planned to examine the antinociceptive efficacy of agomelatine against acute mechanical, thermal, and chemical nociceptive stimuli, as well as to determine the opioid receptor subtypes mediating these effects.. Tail-clip, hot-plate, and acetic acid-induced writhing tests were performed to evaluate anti-nociceptive effect. Besides, possible effect of agomelatine on the motor coordination of animals was assessed with a Rota-rod test.. Agomelatine (40mg/kg and 60mg/kg) significantly prolonged the reaction time of mice in both the tail-clip and hot-plate tests, suggesting the antinociceptive activity is related to both spinal and supraspinal mechanisms. This drug also reduced the number of writhing behaviors indicating the presence of a peripherally mediated antinociceptive effect. Rota-rod testing displayed no notable effect on the motor activity of the animal supporting the conclusion that the observed antinociceptive effect is specific. The agomelatine-induced antinociceptive activity abrogated following pretreatment with naloxone (a non-selective opioid receptor antagonist, 5.48mg/kg, i.p.), which suggested the participation of opioid mechanisms to the antinociception. The possible contribution of μ, δ and ҡ subtypes of opioid receptors to the anti-nociceptive effect were evaluated using naloxonazine (7mg/kg, s.c.), naltrindole (0.99mg/kg, i.p.), and nor-binaltorphimine (1.03mg/kg, i.p.), respectively. Pretreatments using these antagonists abolished the antinociceptive activity of agomelatine in all of the nociceptive test paradigms used, which pointed out that μ, δ, and ҡ opioid receptors participated to the action of agomelatine on pain.. These results demonstrated the therapeutic potential of agomelatine in the treatment of pain disorders.

Topics: Acetamides; Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Mice; Motor Activity; Naloxone; Naltrexone; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Rotarod Performance Test

Most opioid receptor agonists have abuse potential, and the rewarding effects of opioids can be reduced in the presence of pain. While each of the enantiomers of pentazocine has a differential pharmacologic profile, (±)-pentazocine has been used clinically for the treatment of pain. However, little information is available regarding which components of pentazocine are associated with its rewarding effects, and whether the (±)-pentazocine-induced rewarding effects can be suppressed under pain. Therefore, the present study was performed to investigate the effects of pain on the acquisition of the rewarding effects of (±)-pentazocine, and to examine the mechanism of the rewarding effects of (±)-pentazocine using the conditioned place preference paradigm. (±)-Pentazocine and (-)-pentazocine, but not (+)-pentazocine, produced significant rewarding effects. Even though the rewarding effects induced by (±)-pentazocine were significantly suppressed under pain induced by formalin, accompanied by increase of preprodynorphin mRNA levels in the nucleus accumbens, a high dose of (±)-pentazocine produced significant rewarding effects under pain. In the normal condition, (±)-pentazocine-induced rewarding effects were blocked by a low dose of naloxone, whereas the rewarding effects induced by high doses of pentazocine under pain were suppressed by naltrindole (a δ-opioid receptor antagonist). Interestingly, (±)-pentazocine did not significantly affect dopamine levels in the nucleus accumbens. These findings suggest that the rewarding effects of (-)-pentazocine may contribute to the abuse potential of (±)-pentazocine through μ- as well as δ-opioid receptors, without robust activation of the mesolimbic dopaminergic system. We also found that neural adaptations can reduce the abuse potential of (±)-pentazocine under pain.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Conditioning, Psychological; Dose-Response Relationship, Drug; Isomerism; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Pain; Pentazocine; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu; Reward

In anesthetized rats and conscious humans, a gentle touch using a soft disc covered with microcones (with a texture similar to that of a finger), but not with a flat disc, inhibits nociceptive somatocardiac reflexes. Such an inhibitory effect is most reliably evoked when touch is applied to the skin ipsilateral and closest to nociceptive inputs. However, the mechanism of this inhibition is not completely elucidated. We aimed to clarify the types of cutaneous afferent fibers and spinal opioid receptors that contribute to antinociceptive effects of microcone touch.. The present study comprised two experiments with urethane-anesthetized rats. In the first experiment, unitary activity of skin afferent fibers was recorded from the saphenous nerve, and responses to a 10-min touch using a microcone disc and a flat disc (control) were compared. Greater discharge rate during microcone touch was observed in low-threshold mechanoreceptive Aδ and C afferent units, whereas many Aβ afferents responded similarly to the two types of touch. In the second experiment, the effect of an intrathecal injection of opioid receptor antagonists on the inhibitory effects of microcone touch on heart rate responses to noxious heat stimulation was examined. The magnitude of the heart rate response was significantly reduced by microcone touch in rats that received saline or naltrindole (δ-opioid receptor antagonist) injections. However, such an inhibition was not observed in rats that received naloxone (non-selective opioid receptor antagonist) or Phe-Cys-Tyr-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; μ-opioid receptor antagonist) injections.. Microcone touch induced greater responses of low-threshold mechanoreceptive Aδ and C afferent units than control touch. The antinociceptive effect of microcone touch was abolished by intrathecal injection of μ-opioid receptor antagonist. These results suggest that excitation of low-threshold mechanoreceptive Aδ and C afferents produces the release of endogenous μ-opioid ligands in the spinal cord, resulting in the inhibition of nociceptive transmission that contributes to somatocardiac reflexes.

Topics: Analgesics, Opioid; Animals; Heart Rate; Hot Temperature; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Management; Rats, Wistar; Receptors, Opioid; Reflex; Skin; Spinal Cord; Touch

The perception of pain and its inhibition varies considerably between individuals, and this variability is still unexplained. The aim of the present study is to determine whether functional interactions between opioid receptors are involved in the inter-individual variability in the sensitivity to μ-opioid receptor agonists.. Anti-nociceptive tests, radioligand binding, stimulation of [(35) S]GTP-γ-S binding, inhibition of cAMP production and co-immunoprecipitation experiments were performed in two strains of rat (Sprague-Dawley bred at our university - SDU - and Wistar) that differ in their sensitivity to opioids.. The increased anti-nociceptive potency of µ-opioid receptor agonists in SDU rats was reversed by the δ-opioid receptor antagonist, naltrindole. Inhibition of the binding of [(3) H] naltrindole by µ-opioid receptor agonists was different in brain membranes from SDU and Wistar rats. Differences were also evident in the effect of δ-opioid receptor ligands on the binding of [(35) S]GTP-γ-S stimulated by µ-opioid receptors agonists. No strain-related differences were detected in spinal cord membranes. The potency of morphine to inhibit cAMP production in brain membranes varied between the strains, in the presence of deltorphin II and naltrindole. Co-immunoprecipitation experiments demonstrated that δ-opioid receptors were associated with μ-opioid receptors to a higher extent in brain synaptosomal fractions from SDU than in those from Wistar rats.. There was increased supraspinal cross-talk between μ and δ-opioid receptors in SDU, as compared with Wistar rats. This was related to an enhanced sensitivity to anti-nociception induced by µ-opioid receptor agonists.

Topics: Analgesics, Opioid; Animals; Brain; Cyclic AMP; Disease Models, Animal; Guanosine 5'-O-(3-Thiotriphosphate); Immunoprecipitation; Male; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor Cross-Talk; Receptors, Opioid, delta; Receptors, Opioid, mu; Species Specificity; Spinal Cord

In this study we analyzed the mechanisms underlying celecoxib-induced analgesia in a model of inflammatory pain in rats, using the intracerebroventricular (i.c.v.) administration of selective opioid and cannabinoid antagonists.. Analgesic effects of celecoxib were prevented by selective μ-(β-funaltrexamine) and δ-(naltrindole), but not κ-(nor-binaltorphimine) opioid antagonists, given i.c.v. 30 min before celecoxib. Similar pretreatment with AM 251, but not SR 144528, cannabinoid CB(1) and CB(2) receptor antagonists, respectively, prevented celecoxib-induced analgesia. The fatty acid amide hydrolase inhibitor, URB 597, also prevented celecoxib-induced analgesia.. Our data provided further evidence for the involvement of endogenous opioids and revealed a new cannabinoid component of the mechanism(s) underlying celecoxib-induced analgesia.

Topics: Analgesics; Animals; Carrageenan; Celecoxib; Central Nervous System; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Inflammation; Male; Naltrexone; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides

The therapeutic potential of snake venoms for pain control has been previously demonstrated. In the present study, the antinociceptive effects of Micrurus lemniscatus venom (MlV) were investigated in experimental models of pain. The antinociceptive activity of MIV was evaluated using the writhing, formalin, and tail flick tests. Mice motor performance was assessed in the rota rod and open field tests. In a screening test for new antinociceptive substances--the writhing test--oral administration of MlV (19.7-1600 μg/kg) produced significant antinociceptive effect. The venom (1600 μg/kg) also inhibited both phases of the formalin test, confirming the antinociceptive activity. The administration of MlV (1600 μg/kg) did not cause motor impairment in the rota rod and open field tests, which excluded possible non-specific muscle relaxant or sedative effects of the venom. The MIV (177-1600 μg/kg) also increases the tail flick latency response, indicating a central antinociceptive effect for the venom. In this test, the MlV-induced antinociceptive effect was long-lasting and higher than that of morphine, an analgesic considered the gold standard. In another set of experiments, the mechanisms involved in the venom-induced antinociception were investigated through the use of pharmacological antagonists. The MlV (1600 μg/kg) antinociceptive effect was prevented by naloxone (5 mg/kg), a non-selective opioid receptor antagonist, suggesting that this effect is mediated by activation of opioid receptors. In addition, the pre-treatment with the μ-opioid receptor antagonist CTOP (1 mg/kg) blocked the venom antinociceptive effect, while the k-opioid receptor antagonist nor-BNI (0.5 mg/kg) or the δ-opioid receptor antagonist naltrindole (3 mg/kg) only partially reduced the venom-induced antinociception. The present study demonstrates, for the first time, that oral administration of M. lemniscatus venom, at doses that did not induce any motor performance alteration, produced potent and long-lasting antinociceptive effect mediated by activation of opioid receptors.

Topics: Administration, Oral; Analgesics; Animals; Elapid Venoms; Elapidae; Male; Mice; Morphine; Naltrexone; Pain; Pain Measurement; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu

We have previously demonstrated an opioid link in nucleus accumbens (NAc) that mediates antinociception produced by a novel ascending pain modulation pathway. For example, noxious stimulation induces heterosegmental antinociception that is mediated by both mu- and delta-opioid receptors in NAc. However, spinal intrathecal administration of the mu-receptor agonist [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) also induces heterosegmental antinociception. The aim of the present study in the rat was to identify the intra-NAc opioid receptors that mediate the antinociceptive effects of spinally administered DAMGO and also to determine the effect of NAc efferent activity on nociception. Intra-NAc administration of either the mu-opioid receptor antagonist Cys(2),Tyr(3), Orn(5),Pen(7)amide (CTOP) or the delta-opioid receptor antagonist naltrindole blocked the antinociceptive effect of spinally administered DAMGO on the jaw-opening reflex (JOR). Injection of quaternary lidocaine (QX-314) attenuated the JOR, suggesting that the output of NAc is pronociceptive. In support of this, intra-NAc injection of the excitatory amino acid agonist kainate enhanced the JOR. Thus, it is possible to modulate activity in NAc to bidirectionally attenuate or enhance nociception, suggesting a potential role for NAc in setting nociceptive sensitivity.

Topics: Analysis of Variance; Animals; Electrodes, Implanted; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Spinal; Lidocaine; Male; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Pain; Pain Measurement; Pain Perception; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Somatostatin; Spinal Cord

The central nucleus of amygdala (CeA) is a very important brain structure involved in multiple physiological functions, especially in pain modulation. There are high densities of galanin and galanin receptors found in the CeA. The present study was performed to explore the antinociceptive effects of galanin in the CeA of rats, and possible involvements of opioid receptors in the galanin-induced antinociception. Intra-CeA injection of galanin induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations in rats. Interestingly, the amtinociceptive effect induced by intra-CeA injection of galanin was blocked by intra-CeA injection of naloxone, a common opioid receptor antagonist, indicating an involvement of opioid receptors in the galanin-induced antinociception in the CeA of rats. Moreover, intra-CeA injection of either selective mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) or delta-opioid receptor antagonist naltrindole, but not kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI), significantly attenuated the galanin-induced increases in HWLs in the CeA of rats. Taken together, the results demonstrate that galanin induces antinociceptive effects in the CeA of rats, and both mu- and delta-opioid receptors are involved in the galanin-induced antinociception.

Topics: Amygdala; Animals; Galanin; Hindlimb; Hot Temperature; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

Nitrous oxide (N(2)O)-induced analgesia is thought to be mediated by endogenous opioids. We previously showed that the mu-opioid receptor is not required for the analgesic action of N(2)O in mice using a gene knockout approach. In this study, we examined the effect of kappa- (KOP)- or delta-opioid receptor (DOP)-selective antagonists on N(2)O-induced analgesia. The analgesic effect of N(2)O was evaluated using a writhing test. Male C57BL/6 mice aged 7-8 weeks were assigned to control, N(2)O, KOP agonist, and DOP agonist groups. According to the group assignment, mice were pretreated with a KOP antagonist, nor-binaltorphimine (nor-BNI), a DOP antagonist, naltrindole hydrochloride (NTI), a KOP agonist U50488, and a DOP agonist SNC80. Mice in the control, KOP agonist, and DOP agonist groups were exposed to 25% oxygen/75% nitrogen for 30 min, and mice in the N(2)O group were exposed to 25% oxygen/75% N(2)O for 30 min. Nor-BNI [10 mg kg(-1), subcutaneously (s.c.)] significantly suppressed the analgesic effect of N(2)O and U50488. In contrast, NTI (10 mg kg(-1) s.c.) did not significantly affect the analgesic action of N(2)O, but almost completely inhibited the analgesic effect of SNC80. These results suggest that KOP plays an important role in the analgesic effect of N(2)O in mice.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics, Non-Narcotic; Animals; Benzamides; Male; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Nitrous Oxide; Pain; Piperazines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Treatment Outcome

Delta opioid agonists can selectively enhance the antinociceptive effects of mu opioid agonists without enhancing some other, potentially undesirable mu agonist effects. However, the degree of delta receptor efficacy required to produce this profile of interactions is unknown. To address this issue, the present study examined interactions produced by the mu agonist fentanyl and the intermediate-efficacy delta opioid MSF61 in rhesus monkeys. For comparison, interactions were also examined between fentanyl and the relatively high-efficacy delta agonist SNC243A and the delta antagonist naltrindole, which has negligible efficacy at delta receptors. Two different behavioral procedures were used: (a) a warm-water tail-withdrawal assay of thermal nociception, and (b) an assay of schedule-controlled responding for food reinforcement. Drug interactions within each procedure were evaluated using dose-addition analysis to compare experimental results with expected additivity. Drug interactions across procedures were evaluated using dose-ratio analysis to assess relative potencies to produce antinociception vs. response-rate suppression. As expected, dose-addition analysis found that fentanyl/SNC243A interactions were superadditive in the assay of antinociception but additive in the assay of schedule-controlled responding. Conversely, fentanyl/MSF61 interactions were generally additive in both procedures, and fentanyl/naltrindole interactions were additive or subadditive in both procedures. Dose-ratio analysis found that fentanyl alone produced antinociception and rate suppression with similar potencies. Some fentanyl/SNC243A mixtures produced antinociception with up to 4-fold greater potency than rate-suppression. However, fentanyl/MSF61 and fentanyl/naltrindole mixtures produced antinociception with lower potency than rate suppression. These results suggest that relatively high delta receptor efficacy is required for mu/delta antinociceptive synergy.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Interactions; Fentanyl; Hot Temperature; Ligands; Macaca mulatta; Naltrexone; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu

The antinociceptive effects of the selective noradrenaline reuptake inhibitor antidepressant reboxetine and its interaction with various opioid and noradrenaline receptor subtypes were evaluated. Reboxetine (i.p.) induced a weak dose-dependent antinociceptive effect in acute pain, using the hotplate model. The reboxetine-induced antinociception was significantly inhibited by the opioid receptor antagonists naloxone, nor-BNI, naltrindole and b-FNA, implying a non-selective role for the opioid receptors in the reboxetine's antinociceptive effect. The adrenergic antagonists yohimbine and phentolamine attenuated to some extent the reboxetine-induced antinociception, implying a minor adrenergic mechanism of antinociception. The addition of opioid or alpha2 agonists, did not potentiate the antinociception effect of reboxetine. Thus, it seems that reboxetine possesses a weak antinociceptive effect, mediated by non-selective opioid receptors and influenced somewhat by noradrenaline alpha2 receptors. These results suggest that reboxetine as monotherapy does not have sufficient efficacy in the management of acute pain. However, further research is needed in order to establish its possible use alone or in combination with other antidepressants or analgesics in the amelioration of chronic pain disorders.

Topics: Adrenergic Antagonists; Analgesics; Animals; Antidepressive Agents; Clonidine; Disease Models, Animal; Drug Interactions; Male; Mice; Mice, Inbred ICR; Morphine; Morpholines; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Reboxetine; Receptors, Opioid, mu

To enhance analgesia, combination of analgesics drugs of proven efficacy is a strategy which is accompanied by a reduction of adverse effects. The present study was undertaken to characterize the antinociceptive interaction of morphine with different non-steroidal anti-inflammatory drugs (NSAIDs) using isobolographic analysis and the writhing test of mice. One of the possible mechanisms of action of spinally administered morphine with non-steroidal antiinflammatory drugs was investigated using the DOR antagonist naltrindole. The study demonstrated a synergistic antinociception of spinal administered combinations of morphine with the following NSAIDs agents: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supraadditive effect seems to be independent of the selectivity of each NSAIDs to inhibit COX-1 or COX-2. The findings of the present work suggest that the combinations of opioids and non-steroidal anti-inflammatory drugs have a direct action on spinal processing of the nociceptive information, which may achieved by additional mechanisms independent of prostaglandin synthesis inhibition and/or activation of opioid receptors. The lack of effect of naltrindole to modify the analgesic activity of the combination of opioids and NSAIDs indicates that others pain regulatory systems are involved in this central action. Therefore, these combinations could be a viable alternative to clinical pain management, especially trough multimodal analgesia.

Topics: Analgesics, Opioid; Animals; Cyclooxygenase Inhibitors; Drug Synergism; Injections, Spinal; Male; Mice; Mice, Inbred Strains; Morphine; Naltrexone; Pain; Receptors, Opioid, delta; Spinal Cord

The aim of the present study was to evaluate the antinociceptive effect of the novel pyrazoline methyl ester: 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4).. The effect of MPF4 was assessed in two models of pain: arthritic pain caused by Complete Freund's Adjuvant (CFA) and postoperative pain caused by surgical incision in mice.. MPF4 given intraperitoneally (1.0 mmol/kg, i.p.) produced marked antinociception in inflammatory allodynia caused by CFA. The antinociceptive effect produced by MPF4 was reversed with the pre-treatment of animals with naloxone or naltrindole. Oral administration of MPF4 (1.0 mmol/kg, p.o), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.) also produced an anti-allodynic effect. However, none of the compounds evaluated reversed the paw edema produced by CFA. Moreover, MPF4, dipyrone and morphine also produced an anti-allodynic effect in the surgical incisional pain model. The maximal inhibitions obtained with preemptive drug treatment were 66+/-7%, 73+/-9% and 88+/-8% for MPF4 (1.0 mmol/kg, p.o.), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.), respectively. The maximal inhibitions obtained with curative drug treatment were 53+/-9%, 83+/-7% and 84+/-7%, for MPF4, dipyrone and morphine, respectively. Unlike indomethacin, MPF4 did not induce gastric lesions at the dose that caused the highest antinociception (1.0 mmol/kg, p.o). The anti-allodynic action of MPF4, dipyrone and morphine was not associated with impairment of motor activity.. The results of the present study suggest that MPF4 represents a potential target for the development of new drugs to treat persistent inflammatory pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Dipyrone; Freund's Adjuvant; Indomethacin; Inflammation; Male; Mice; Morphine; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain, Postoperative; Postural Balance; Pyrazoles; Stomach Ulcer

The present study investigated the role of peripheral opioid receptors in mustard oil-induced nociceptive behavior and inflammation in the masseter muscles of lightly anesthetized rats. Experiments were carried out on male Sprague-Dawley rats weighing between 300 and 400 g. After initial anesthesia with sodium pentobarbital (40 mg/kg, i.p.), one femoral vein was cannulated and connected to an infusion pump for the intravenous infusion of sodium pentobarbital. The rate of infusion was adjusted to provide a constant level of anesthesia. Mustard oil (MO, 30 microl) was injected into the mid-region of the left masseter muscle via a 30-gauge needle. Intramuscularly-administered morphine significantly reduced shaking behavior but not MO-induced inflammation. Intramuscular pretreatment with naloxone, an opioid receptor antagonist, reversed antinociception produced by intramuscularly-administered morphine, while intracisternal administration of naloxone did not affect the antinociception of peripheral morphine. Pretreatment with d-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu opioid receptor antagonist, but not naltrindole, a delta opioid receptor antagonist, nor norbinaltorphimine (nor-BNI), a kappa opioid receptor antagonist, reversed intramuscularly-administered morphine-induced antinociception. These results indicate that intramuscularly-administered morphine produces antinociception in craniofacial muscle nociception and that this intramuscularly-administered morphine-induced antinociception is mediated by a peripheral mu opioid receptor. Our observations further support the clinical approach of administering opioids in the periphery for the treatment of craniofacial muscle nociception.

Topics: Analgesics; Anesthesia, General; Animals; Inflammation; Injections; Injections, Intramuscular; Male; Masseter Muscle; Morphine; Mustard Plant; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Plant Oils; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Single-Blind Method; Somatostatin

Endomorphin-1 and endomorphin-2 are endogenous peptides that are highly selective for mu-opioid receptors. However, studies of their functional efficacy and selectivity are controversial. In this study, we systematically compared the effects of intrathecal (i.t.) administration of endomorphin-1 and -2 on nociception assays and G protein activation with those of [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), a highly effective peptidic mu-opioid receptor agonist.. Male Sprague-Dawley rats were used. Acute and inflammatory pain models were used to compare the duration and magnitude of antinociception. Agonist-stimulated [(35)S]GTP gamma S binding was used to observe the functional activity at the level of the receptor-G protein in both spinal cord and thalamic membranes. In addition, antagonists selective for each receptor type were used to verify the functional selectivity of endomorphins in the rat spinal cord.. After i.t. administration, endomorphin-1 and -2 produced less antinociceptive effects than DAMGO in the model of acute pain. Concentration-response curves for DAMGO-, endomorphin-1-, and endomorphin-2-stimulated [(35)S]GTP gamma S binding revealed that both endomorphin-1 and -2 produced less G protein activation (i.e., approximately 50%-60%) than DAMGO did in the membranes of spinal cord and thalamus. In addition, i.t. endomorphin-induced antinociception was blocked by mu-opioid receptor selective dose of naltrexone (P < 0.05), but not by delta- and kappa-opioid receptor antagonists, naltrindole and nor-binaltorphimine (P > 0.05).. Endomorphins are partial agonists for G protein activation at spinal and thalamic mu-opioid receptors. Both in vivo and in vitro measurements together suggest that DAMGO is more effective than endomorphins. Spinal endomorphins' antinociceptive efficacy may range between 53% and 84% depending on the intensity and modality of the nociceptive stimulus.

Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Partial Agonism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Spinal; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Spinal Cord; Sulfur Radioisotopes; Thalamus; Time Factors

Sickle cell anemia is a common genetic disorder in African Americans. Opioid analgesics are traditionally the treatment for the severe pain associated with this disease. Here we reveal that the opioid antagonist naloxone possesses potent analgesic activity in two transgenic mouse models of sickle cell anemia (NY1DD and hBERK1) and not in their respective controls (ICR-CD1 and C57BL/6J) when administered by three parenteral routes [intracerebroventricular (i.c.v.), intrathecal, and subcutaneous]. In the NY1DD mice, naloxone (i.c.v.) possessed approximately 300-fold greater potency than morphine (i.c.v.). Other opioid antagonists (naltrexone, norbinaltorphimine, and naltrindole) were substantially less effective in producing analgesia. Naloxone and morphine were synergistic in NY1DD mice, suggesting different receptor systems. Microarray analysis suggested naloxone-induced down-regulation of the CC chemokine receptor (CCR)5 in NY1DD mice but not in control mice. Pretreatment of control mice with CC chemokine ligand 5 [CCL5 (RANTES)] enabled naloxone to produce analgesia similar to that observed in NY1DD mice. Mu opioid receptor knockout mice treated similarly also displayed analgesia. That the effect of CCL5 was specifically related to CCR5 and/or CCR1 activation was demonstrated by antagonism of analgesia with the chemokine antagonist methionylated RANTES. Similar antagonism of naloxone-induced analgesia also was observed when NY1DD mice were pretreated with methionylated RANTES. These results indicate that CCR5/CCR1 receptors are directly or indirectly involved in analgesia produced by naloxone. The present study suggests that naloxone may be clinically useful in the treatment of pain associated with sickle cell disease and other disorders involving inflammation.

Topics: Analgesics; Analgesics, Opioid; Anemia, Sickle Cell; Animals; Chemokine CCL5; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Morphine; Naloxone; Pain; Pain Measurement; Receptors, CCR5

In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED50=1.9 (0.7-5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED80 of (-)-NIH 11082 in the PPQ test [AD50=0.75 (0.26-2.20) mg/kg, s.c]. beta-Funaltrexamine and nor-binaltorphimine, selective mu- and kappa-receptor antagonists, respectively, were inactive versus the ED80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.

Topics: Analgesics, Opioid; Animals; Arthritis, Experimental; Benzomorphans; Female; Hot Temperature; Macaca mulatta; Male; Mice; Mice, Inbred ICR; Morphine Dependence; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Lew; Receptors, Opioid, delta; Stereoisomerism; Substance Withdrawal Syndrome

Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception.. Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a delta-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats.. Both micro and delta antagonists augmented analgesia produced by a sub-maximal (5 microg) or maximal (15 microg) dose of morphine. Administration of the antagonists with morphine (15 microg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency.. Combining ultralow doses of micro- or delta-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of micro- and delta-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Injections, Spinal; Male; Morphine; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Somatostatin

Opioid effects are mediated by central and peripheral opioid receptors. Here we examine the relative contribution of each receptor population to antinociception elicited by systemically administered centrally penetrating opioids, and by loperamide (a peripherally restricted opioid). Nociception (abdominal writhes) was induced by intraperitoneally (i.p.) injected 0.6% acetic acid in mice. We analyzed opioid receptor expression in peritoneum by immunohistochemistry, antinociception after i.p. injected agonists at mu (morphine, loperamide)-, delta (SNC80)- and kappa (U50488)-receptors, and its reversibility by subcutaneously (s.c.) administered centrally penetrating antagonists beta-funaltrexamine (mu), naltrindole (delta) and nor-binaltorphimine (kappa), and by the peripherally restricted antagonist naloxone methiodide (NLXM). NLXM was also injected intracerebroventricularly (i.c.v.) before i.p. loperamide. Mu-, kappa- and, to a lesser degree, delta-receptors were expressed on peripheral nerve terminals in the peritoneum. The anatomical distribution of the opioid receptor staining was very similar to the staining for calcitonin gene-related peptide, a marker of sensory neurons. Morphine, U50488 and, to a lesser degree, SNC80 blocked acetic and acid induced writhes. These effects were reversed by beta-funaltrexamine, nor-binaltorphimine and naltrindole, respectively. NLXM (s.c.) reversed antinociceptive effects of morphine, SNC80 and U50488 by 57%, 80% and 47%, respectively. Loperamide (0.05 mg/kg)-induced antinociception was reversed by s.c. beta-funaltrexamine and NLXM. Loperamide (0.1 mg/kg)-induced antinociception was completely blocked by s.c. beta-funaltrexamine but was only attenuated (by 50%) by s.c. or i.c.v. NLXM. In conclusion, systemically administered centrally penetrating mu-, delta- and kappa-agonists produced a substantial part of antinociception through peripheral opioid receptors. Higher dose loperamide-induced antinociception involved also central opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetic Acid; Analgesics, Non-Narcotic; Analgesics, Opioid; Analysis of Variance; Animals; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Gene Expression; Loperamide; Male; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid

This study examined the role of kappa opioid receptors (KOR) in the mechanism underlying tolerance to the analgesic effects of morphine induced by chronic pain. The analgesic effect of morphine (10 mg kg(-1)), estimated by the tail-flick test in mice, gradually decreased during repeated daily morphine treatment. A significant decrease in the analgesic effect of morphine was seen on the fifth day of repeated morphine treatment compared with the first day. Chronic pain was induced by subcutaneous administration of 2% formalin into the dorsal part of the left hind paw, which significantly inhibited development of tolerance to morphine analgesia. The effect of formalin-induced pain on inhibition of morphine tolerance was reversed by the KOR antagonist nor-binaltorphimine. Furthermore, an antisense oligodeoxynucleotide, but not a missense oligodeoxynucleotide, against KOR completely suppressed the inhibitory effect of formalin-induced pain on morphine tolerance. Naltrindole, an antagonist of delta opioid receptor, did not affect chronic-pain-induced tolerance to morphine. Our findings show that the inhibitory effect of chronic pain on analgesic tolerance to morphine is mediated by KOR rather than delta opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Chronic Disease; Drug Tolerance; Formaldehyde; Male; Mice; Morphine; Naltrexone; Oligonucleotides, Antisense; Pain; Pain Measurement; Pain Threshold; Receptors, Opioid, delta; Receptors, Opioid, kappa; Tail

Clinically, it has been reported that chronic pain induces depression, anxiety, and reduced quality of life. The endogenous opioid system has been implicated in nociception, anxiety, and stress. The present study was undertaken to investigate whether chronic pain could induce anxiogenic effects and changes in the opioidergic function in the amygdala in mice. We found that either injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by sciatic nerve ligation produced a significant anxiogenic effect at 4 weeks after the injection or surgery. Under these conditions, the selective mu-opioid receptor agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO)- and the selective delta-opioid receptor agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)-stimulated [35S]GTPgammaS binding in membranes of the amygdala was significantly suppressed by CFA injection or nerve ligation. CFA injection was associated with a significant increase in the kappa-opioid receptor agonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride (ICI199,441)-stimulated [35S]GTPgammaS binding in membranes of the amygdala. The intracerebroventricular administration and microinjection of a selective mu-opioid receptor antagonist, a selective delta-opioid receptor antagonist, and the endogenous kappa-opioid receptor ligand dynorphin A caused a significant anxiogenic effect in mice. We also found that thermal hyperalgesia induced by sciatic nerve ligation was reversed at 8 weeks after surgery. In the light-dark test, the time spent in the lit compartment was not changed at 8 weeks after surgery. Collectively, the present data constitute the first evidence that chronic pain has an anxiogenic effect in mice. This phenomenon may be associated with changes in opioidergic function in the amygdala.

Topics: Amygdala; Analgesics, Opioid; Analysis of Variance; Animals; Anxiety; Behavior, Animal; Benzamides; Chronic Disease; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Freund's Adjuvant; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Intraventricular; Male; Maze Learning; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pain Measurement; Piperazines; Protein Binding; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reaction Time; Sciatica; Somatostatin; Sulfur Isotopes; Time Factors; Tranquilizing Agents

It is well known that there are three types of opioid receptors, mu- (MOR), delta- (DOR), and kappa-opioid receptor (KOR) in the central nervous system. The present study investigated the involvement of opioid receptors in morphine-induced antinociception in the nucleus accumbens (NAc) of rats. The hindpaw withdrawal latencies to thermal and mechanical stimulation increased markedly after intra-NAc administration of morphine. The antinociceptive effects induced by morphine were dose-dependently inhibited by intra-NAc administration of the non-selective opioid receptor antagonist naloxone. Furthermore, the morphine-induced antinociception was significantly attenuated by subsequent intra-NAc injection of the MOR antagonist beta-funaltrexamine or the KOR antagonist nor-binaltorphimine, but not the DOR antagonist naltrindole. The results indicate that MOR and KOR, but not DOR are involved in the morphine-induced antinociception in the NAc of rats.

Topics: Analgesics, Opioid; Animals; Male; Morphine; Naloxone; Naltrexone; Nucleus Accumbens; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

[Dmt1]Endomorphin-1 is a novel analogue of the potent mu-opioid agonist endomorphin-1. Given the physiological role of endomorphin-1 in vivo, this compound was investigated to determine if the antinociception occurred through systemic, supraspinal or in a combination of both neuronal pathways. This compound exhibited a potent dose-dependent effect intracerebroventricularly in both spinal and supraspinal regions, and was blocked by opioid antagonist naloxone, which verified the involvement of opioid receptors. Specific opioid antagonists characterized the apparent receptor type: beta-funaltrexamine (mu1/mu2-irreversible antagonist) equally inhibited spinal- and central-mediated antinociception; on the other hand, naloxonazine (mu1-subtype) was ineffective in both neural pathways and naltrindole (delta-selective antagonist) partially (26%), though not significantly, blocked only the spinal-mediated antinociception. Therefore, spinal antinociception was primarily triggered by mu2-subtypes without involvement of mu1-opioid receptors; however, although a slight enhancement of antinociception by delta-receptors cannot be completely ruled out since functional bioactivity indicated mixed mu-agonism/delta-antagonism. In terms of the CNS action, [Dmt1]endomorphin-1 appears to act through mu2-opioid receptor subtypes.

Topics: Analgesia; Animals; Brain; Guinea Pigs; Ileum; Injections, Intraventricular; Male; Mice; Naloxone; Naltrexone; Oligopeptides; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord; Tail; Vas Deferens

The potent opioid [Dmt1]endomorphin-2 (Dmt-Pro-Phe-Phe-NH2) differentiated between the opioid receptor subtypes responsible for the antinociception elicited by endomorphin-2 in mice. Antinociception, induced by the intracerebroventricular administration of [Dmt1]endomorphin-2 and inhibited by various opioid receptor antagonists [naloxone, naltrindole, beta-funaltrexamine, naloxonazine], was determined by the tail-flick (spinal effect) and hot-plate (supraspinal effect) tests. The opioid receptor subtypes involved in [Dmt1]endomorphin-2-induced antinociception differed between these in vivo model paradigms: naloxone (non-specific opioid receptor antagonist) and beta-funaltrexamine (irreversible mu1/mu2-opioid receptor antagonist) blocked antinociception in both tests, although stronger inhibition occurred in the hot-plate than the tail-flick test suggesting involvement of other opioid receptors. Consequently, we applied naloxonazine (mu1-opioid receptor antagonist) that significantly blocked the effect in the hot-plate test and naltrindole (delta-opioid receptor antagonist), which was only effective in the tail-flick test. The data indicated that [Dmt1]endomorphin-2-induced spinal antinociception was primarily mediated by both mu2- and delta-opioid receptors, while a supraspinal mechanism involved only mu1/mu2-subtypes.

Topics: Analgesia; Animals; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Hot Temperature; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Naloxone; Naltrexone; Nociceptors; Oligopeptides; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu; Tail; Time Factors

The effect of oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice was examined. The antinociceptive response was assessed by recording the latency in the tail-flick test using the radiant heat from a 50-W projection bulb on the tail. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. When diabetic mice were treated with oxycodone (5 mg/kg, s.c.), the tail-flick latency in diabetic mice was prolonged to the level considerably longer than the baseline latencies of non-diabetic mice. However, s.c. administration of morphine (5 mg/kg) did not produce a significant inhibition of the tail-flick response in diabetic mice. Oxycodone, at doses of 1.25-5.0 mg/kg administered s.c., produced a dose-dependent increase in the tail-flick latencies in both diabetic and non-diabetic mice. The antinociceptive effect of oxycodone was antagonized by pretreatment with a selective delta-opioid receptor antagonist, beta-funaltrexamine (20 mg/kg, s.c.), in both non-diabetic and diabetic mice. In non-diabetic mice, pretreatment with a selective kappa-opioid receptor antagonist, nor-binaltorphimine (20 mg/kg, s.c.) had no effect on the peak antinociceptive effect of oxycodone observed 30 min after administration, however, it slightly but significantly reduced oxycodone-induced antinociception observed 60 and 90 min after administration. On the other hand, pretreatment with nor-binaltorphimine practically abolished the peak (30 min) and persistent (60 and 90 min) antinociceptive effects of oxycodone in diabetic mice. Naltrindole (35 mg/kg, s.c.), a selective delta-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in both non-diabetic and diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by mu- and kappa-opioid receptors in diabetic mice, whereas it may interact primarily with mu-opioid receptors in non-diabetic mice.

Topics: Analgesics, Opioid; Animals; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Morphine; Naltrexone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Time Factors

Intrathecal (i.t.) pretreatment with a low dose (0.3 nmol) of morphine causes an attenuation of i.t. morphine-produced analgesia; the phenomenon has been defined as morphine-induced antianalgesia. The opioid-produced analgesia was measured with the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with low dose (0.3 nmol) of morphine time dependently attenuated i.t. morphine-produced (3.0 nmol) TF inhibition and reached a maximal effect at 45 min. Intrathecal pretreatment with morphine (0.009-0.3 nmol) for 45 min also dose dependently attenuated morphine-produced TF inhibition. The i.t. morphine-induced antianalgesia was dose dependently blocked by the nonselective mu-opioid receptor antagonist (-)-naloxone and by its nonopioid enantiomer (+)-naloxone, but not by endomorphin-2-sensitive mu-opioid receptor antagonist 3-methoxynaltrexone. Blockade of delta-opioid receptors, kappa-opioid receptors, and N-methyl-D-aspartate (NMDA) receptors by i.t. pretreatment with naltrindole, nor-binaltorphimine, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), respectively, did not affect the i.t. morphine-induced antianalgesia. Intrathecal pretreatment with antiserum against dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, beta-endorphin, cholecystokinin, or substance P also did not affect the i.t. morphine-induced antianalgesia. The i.t. morphine pretreatment also attenuated the TF inhibition produced by opioid muagonist [D-Ala2, N-Me-Phe4,Gly-ol5]-enkephalin, delta-agonist deltorphin II, and kappa-agonist U50,488H. It is concluded that low doses (0.009-0.3 nmol) of morphine given i.t. activate an antianalgesic system to attenuate opioid mu-, delta-, and kappa-agonist-produced analgesia. The morphine-induced antianalgesia is not mediated by the stimulation of opioid mu-, delta-, or kappa-receptors or NMDA receptors. Neuropeptides such as dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, beta-endorphin, cholecystokinin, and substance P are not involved in this low-dose morphine-induced antianalgesia.

Topics: Analgesia; Animals; beta-Endorphin; Dizocilpine Maleate; Drug Interactions; Drug Tolerance; Dynorphins; Enkephalins; Male; Mice; Morphine; Naloxone; Naltrexone; Oligopeptides; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord; Substance P

The clinical practice of spinal morphine administration for pain relief is based on observations in animals that opioid receptors exist in the spinal cord and intrathecal injections of opioids in those species (mostly rats) lead to antinociceptive effects. Clinicians are well aware that administration of spinal opioids is associated with side-effects, such as nausea and respiratory depression, that indicate supraspinal spread of the drug administered. Those observations call into question how much of the observed pain relief is due to action of the drug in the brain. This study investigated the spinal cord actions of morphine given intrathecally to rats in a model that allows investigation of drug-receptor interaction at the spinal cord level. Experiments were performed on male Wistar rats with chronically implanted lumbar subarachnoid catheters.. Nociceptive thresholds were measured in rats given morphine intrathecally alone and in combination with intrathecal injections of selective opioid receptor antagonists: beta-funaltrexamine (mu), naltrindole (delta) and nor-binaltorphimine (kappa).. Intrathecal morphine caused dose-related antinociceptive effects that were reversed totally by naloxone. Intrathecal beta-funaltrexamine and naltrindole did not reverse the effects of intrathecal morphine. However, intrathecal nor-binaltorphimine did reverse the electrical current threshold effects of morphine but not tail flick latency.. Antinociception following intrathecal morphine involves spinal and supraspinal opioid receptors. The tail flick effect described in rat experiments involves actions at opioid receptors in the brain that override any action that may be caused by combination of morphine with mu-opioid receptors in the spinal cord.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Injections, Spinal; Male; Models, Animal; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Random Allocation; Rats; Rats, Wistar; Reaction Time; Receptors, Opioid; Spinal Cord; Tail

Our study addressed the hypothesis that spinal release of endogenous opioids underlies Delta9-tetrahydrocannabinol (Delta9-THC)-induced antinociception in Freund's adjuvant-induced arthritic and nonarthritic rats. The paw-pressure test was used to assess the antinociceptive effects of Delta9-THC versus those of morphine, and opioid and cannabinoid receptor-selective antagonists were used to characterize the involved receptors. Cerebrospinal fluid was collected after Delta9-THC injection (i.p.) for the measurement of endogenous opioid peptides. Our results indicate that morphine or Delta9-THC is equally potent and efficacious in both nonarthritic and arthritic rats. Delta9-THC-induced antinociception is attenuated by the kappa opioid receptor antagonist, nor-binaltorphimine, in arthritic rats only. Delta9-THC induces increased immunoreactive dynorphin A (idyn A) levels in nonarthritic rats while decreasing idyn A in arthritic rats. We hypothesize that the elevated idyn A level in arthritic rats contributes to hyperalgesia by interaction with N-methyl-D-aspartate receptors, and that Delta9-THC induces antinociception by decreasing idyn A release.

Topics: Animals; Arthritis, Experimental; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Dronabinol; Dynorphins; Enkephalin, Leucine; Enkephalin, Methionine; Freund's Adjuvant; Injections, Intradermal; Injections, Intraperitoneal; Male; Morphine; Mycobacterium; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Opioid; Rimonabant

Oxymorphazole (17-methyl-6,7-dehydro-3,14-dihydroxy-4,5 alpha-epoxy-6,7:3',4'-pyrazolomorphinan), a hydrophilic opioid, given intracerebroventricularly (2.5-50 nmol) or intrathecally (0.3-5 nmol) dose-dependently produced tail-flick inhibition in male CD-1 mice. However, oxymorphazole given subcutaneously even at high doses (10-80 mg/kg) produced weak tail-flick inhibition. Oxymorphazole given intraperitoneally (0.1 to 10 mg/kg) dose-dependently inhibited abdominal constriction response induced by intraperitoneally injection of 0.6% acetic acid. Oxymorphazole given intracerebroventricularly (25 nmol) or intrathecally (5 nmol) induced tail-flick inhibition was blocked by pretreatment with the mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Orn-Thr-Pen-Thr-NH2, but not kappa-opioid receptor antagonist nor-binaltrophimine. The delta-opioid receptor antagonist, naltrindole, blocked the tail-flick inhibition induced by oxymorphazole given intrathecally but not intracerebroventricularly. The inhibition of the abdominal constriction response by oxymorphazole given intraperitoneally was blocked by intraperitoneally pretreatment with naloxone, but not naltrindole or nor-binaltrophimine. Thus, oxymorphazole given systemically produces antinociception only with the abdominal constriction test, but not the tail-flick test, suggesting that it produces the antinociception at the peripheral sites when administered systemically. The oxymorphazole-induced antinociception is mainly mediated by the stimulation of mu-opioid receptors when given either centrally or systemically and also the delta-opioid receptors when given intrathecally. The lack of central antinociceptive effect of oxymorphazole given systemically may have interesting clinical implications.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Spinal; Male; Mice; Morpholines; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu; Somatostatin; Time Factors

The present study was conducted on rats with inflammation induced by subcutaneous injection of carrageenan into the left hindpaw. Intrathecal administration of oxytocin produced dose-dependent increases in the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats with inflammation. The antinociceptive effect of oxytocin was blocked by intrathecal administration of atosiban, a selective oxytocin antagonist, indicating that oxytocin receptor mediates oxytocin-induced antinociception in the spinal cord. The oxytocin-induced antinociceptive effect was attenuated by intrathecal administration of the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Furthermore, the antinociceptive effect of oxytocin was attenuated by intrathecal injections of the mu-receptor antagonist beta-funaltrexamine and the kappa-receptor antagonist nor-binaltorphimine, but not by the delta-receptor antagonist naltrindole, illustrating that mu- and kappa-receptors, but not delta-receptor, are involved in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Moreover, intrathecal administration of atosiban alone induced a hyperalgesia in rats with inflammation, indicating that endogenous oxytocin is involved in the transmission and regulation of nociceptive information in the spinal cord of rats with inflammation. The present study showed that both exogenous and endogenous oxytocin displayed antinociception in the spinal cord in rats with inflammation, and mu- and kappa-receptors were involved in oxytocin-induced antinociception.

Topics: Analgesics; Animals; Carrageenan; Hot Temperature; Inflammation; Injections, Spinal; Male; Naloxone; Naltrexone; Narcotic Antagonists; Oxytocin; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Wistar; Spinal Cord; Vasotocin

Agonists at delta, mu, and kappa opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of delta + mu and delta + kappa agonists in rhesus monkeys (n = 4-5) using two behavioral procedures, an assay of schedule-controlled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the mu agonists methadone, fentanyl, morphine, and nalbuphine; and the kappa agonists (5alpha,7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 + mu agonists produced additive or subadditive effects, whereas SNC80 + kappa agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas mu and kappa agonists produced dose-dependent antinociception. SNC80 + mu agonist mixtures produced superadditive effects manifested as leftward shifts in mu agonist dose-effect curves. This synergism was antagonized by the delta-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of mu agonist antinociception was delta receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective kappa agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective kappa agonist bremazocine. These results suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint.

Topics: Analgesics, Opioid; Animals; Benzamides; Benzeneacetamides; Benzomorphans; Conditioning, Operant; Dose-Response Relationship, Drug; Drug Interactions; Hot Temperature; Macaca mulatta; Male; Naltrexone; Narcotic Antagonists; Pain; Piperazines; Pyrrolidines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reinforcement Schedule

The present study investigates the involvement of opioid receptors in the antinociceptive effects of nociceptin in the spinal cord of the rat. Intrathecal administrations of 5 and 10 nmol of nociceptin significantly increase the withdraw response latencies to noxious thermal and mechanical stimulations. This nociceptin-induced antinociceptive effect is significantly attenuated by intrathecal injection of (Nphe(1))nociceptin(1-13)-NH(2), a selective antagonist of the nociceptin receptor (opioid receptor-like receptor ORL1), indicating an ORL1 receptor-mediated mechanism. This antinociceptive effect is also significantly attenuated by intrathecal injections of naloxone (a nonselective opioid receptor antagonist), naltrindole (a selective delta-opioid receptor antagonist), and beta-funaltrexamine (a selective mu-opioid receptor antagonist) in a dose-dependent manner, but not by the selective kappa-opioid receptor antagonist norbinaltorphimine. Since it is unlikely that nociceptin acts by direct binding to opioid receptors, these results suggest a possible interaction between the nociceptin/ORL1 and opioid systems in the dorsal horn of the rat spinal cord.

Topics: Animals; Endorphins; Hindlimb; Hot Temperature; Injections, Spinal; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptin; Nociceptors; Opioid Peptides; Pain; Pain Measurement; Peptide Fragments; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord

The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor ORL-1, also designated opioid receptor 4 (OP(4)) are involved in the modulation of nociception. Using OP(4)-knockout mice, we have studied their response following opioid receptor stimulation and under neuropathic conditions.In vas deferens from wild-type and OP(4)-knockout mice, DAMGO (mu/OP(3) agonist), deltorphine II (delta/OP(1) agonist) and (-)-U-50488 (kappa/OP(2) agonist) induced similar concentration-dependent inhibition of electrically-evoked contractions. Naloxone and naltrindole (delta/OP(1) antagonists) shifted the curves of DAMGO (pA(2)=8.6) and deltorphine II (pA(2)=10.2) to the right, in each group. In the hot-plate assay, N/OFQ (10 nmol per mouse, i.t.) increased baseline latencies two-fold in wild-type mice while morphine (10mg/kg, s.c.), deltorphine II (10 nmol per mouse, i.c.v.) and dynorphin A (20 nmol per mouse, i.c.v.) increased hot-plate latencies by about four- to five-fold with no difference observed between wild-type and knockout mice. Furthermore, no change was evident in the development of the neuropathic condition due to chronic constriction injury (CCI) of the sciatic nerve, after both thermal and mechanical stimulation. Altogether these results suggest that the presence of OP(4) receptor is not crucial for (1) the development of either acute or neuropathic nociceptive responses, and for (2) the regulation of full receptor-mediated responses to opioid agonists, even though compensatory mechanisms could not be excluded.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Male; Mice; Mice, Knockout; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Oligopeptides; Opioid Peptides; Pain; Receptors, Opioid; Time Factors; Vas Deferens

The antinociceptive effects of intracerebroventricularly (i.c.v.) administered dynorphin A, an endogenous agonist for kappa-opioid receptors, in combination with various protease inhibitors were examined using the mouse formalin test in order to clarify the nature of the proteases involved in the degradation of dynorphin A in the mouse brain. When administered i.c.v. 15 min before the injection of 2% formalin solution into the dorsal surface of a hindpaw, 1-4 nmol dynorphin A produced a dose-dependent reduction of the nociceptive behavioral response consisting of licking and biting of the injected paw during both the first (0-5 min) and second (10-30 min) phases. When co-administered with p-hydroxymercuribenzoate (PHMB), a cysteine protease inhibitor, dynorphin A at the subthreshold dose of 0.5 nmol significantly produced an antinociceptive effect during the second phase. This effect was significantly antagonized by nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-opioid receptor antagonist. At the same dose of 0.5 nmol, dynorphin A in combination with phosphoramidon, an endopeptidase 24.11 inhibitor, produced a significant antinociceptive effect during both phases. The antinociceptive effect was significantly antagonized by naltrindole, but not by nor-binaltorphimine. Phenylmethanesulfonyl fluoride (PMSF), a serine protease inhibitor, bestatin, a general aminopeptidase inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, were all inactive. The degradation of dynorphin A by mouse brain extracts in vitro was significantly inhibited only by the cysteine protease inhibitors PHMB and N-ethylmaleimide, but not by PMSF, phosphoramidon, bestatin or captopril. The present results indicate that cysteine proteases as well as endopeptidase 24.11 are involved in two steps in the degradation of dynorphin A in the mouse brain, and that phosphoramidon inhibits the degradation of intermediary delta-opioid receptor active fragments enkephalins which are formed from dynorphin A.

Topics: Animals; Brain; Cell Extracts; Drug Interactions; Dynorphins; Glycopeptides; Hydroxymercuribenzoates; Injections, Intraventricular; Mice; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Protease Inhibitors; Rats

ATP-gated K(+) channel openers produce antinociception that is attenuated by opioid receptor antagonists, indicating K-ATP openers produce antinociception, in part, via the release of endogenous opioid peptides. Utilizing the spinal perfusion method, male Sprague-Dawley rats were administered minoxidil intrathecally (i.t.) at doses ranging from 12.5 to 200 microg/rat for 3 min, tested for antinociception using the tail-flick test, and perfused with artificial cerebrospinal fluid (aCSF) to collect endogenous opioid peptides. Endogenous opioid peptide levels were measured by radioimmunoassay. Naltrindole, a delta-opioid receptor antagonist, at 4 mg/kg, subcutaneously (s.c.), blocked minoxidil-induced antinociception. beta-Funaltrexamine, a mu-opioid receptor antagonist, at 100 microg/rat, partially blocked minoxidil, whereas the kappa-opioid receptor antagonist nor-binaltorphimine, at a dose of 100 microg/rat, did not attenuate minoxidil. Although antagonists of the mu- and delta-opioid receptor attenuated minoxidil-induced antinociception, there was no increase in beta-endorphin, an endogenous ligand with affinity for both micro- and delta-opioid receptors or [Leu(5)]enkephalin, an endogenous ligand with affinity for delta-opioid receptors.

Topics: Adenosine Triphosphate; Animals; Dose-Response Relationship, Drug; Male; Minoxidil; Naltrexone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Pain; Potassium Channels; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Spinal Cord; Vasodilator Agents

1. RB 101, a complete inhibitor of enkephalin-catabolizing enzymes, has been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a cholecystokinin-B (CCK-B) receptor antagonist has been shown to strongly enhance its antinociceptive effect in normal rats. In this work, we determined whether RB 101 was able to reduce hyperalgesia and allodynia in diabetic rats, a model of neuropathic pain. The type of opioid receptors (mu or delta) involved was determined using naloxone and naltrindole, respectively, and the interactions between endogenous enkephalins and CCK on nociception control was investigated using coadministration of RB 101 and the CCK-B receptor antagonist CI-988. 2. RB 101 suppressed mechanical hyperalgesia (paw pressure-induced vocalization test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analgesic effect was completely cancelled by naloxone or naltrindole, suggesting that is requires the availability of mu- and/or delta-opioid receptors. 3. The combination of an inactive dose of CI-988 with the lowest effective dose of RB 101 resulted in a stronger increase in the vocalization threshold comparatively to RB 101 alone. 4. The present study demonstrates that the antinociception generated by RB 101 induced by elevation of extracellular levels of endogenous enkephalins, can be extended to neuropathic pain in diabetic rats and that blockade of CCK-B receptors potentiated antinociceptive effects elicited by RB 101.

Topics: Aminopeptidases; Animals; Diabetes Mellitus, Experimental; Disulfides; Drug Synergism; Indoles; Male; Meglumine; Naloxone; Naltrexone; Neprilysin; Pain; Pain Measurement; Phenylalanine; Pressure; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Time Factors; Vocalization, Animal; Weight Loss

There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia.. The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia.. In experiments 1-3, different groups of male, Wistar rats (275-300 g) were administered vehicle, 0. 5, 1.0 or 2.0-nmol doses of the mu-selective antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide (CTOP), the delta-receptor selective antagonist naltrindole, or the kappa-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5 degrees C), once a day for eight consecutive days.. Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI.. These results support the involvement of the mu and delta, but not the kappa, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.

Topics: Animals; Dose-Response Relationship, Drug; Habituation, Psychophysiologic; Male; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Somatostatin

We examined the effects of repeated exposure to forced walking stress for 6 h once a day for 0, 6 and 9 consecutive days on formalin-induced paw licking in mice. In each observation period, stress-induced antinociception (SIA) was observed only in the late phase (from 10 to 30 min), but not in the early phase (from 0 to 10 min) of formalin-induced paw licking in mice. Moreover, it was hard to develop tolerance even by daily exposure to stress for 6 days, although SIA for 9 days decreased compared with those for 0 and 6 days. Naloxone (10 mg/kg), an opioid-receptor antagonist, was effective in reducing the SIA induced by forced walking stress for 6 days and/or 9 days, but not for 0 days. Furthermore, the experiments with selective opioid-receptor antagonists, beta-funaltrexamine (mu) naltrindol (delta), or nor-binaltorphimine (kappa) demonstrated that SIA induced by forced walking stress for 9 successive days may be mediated through opioid delta- and kappa-receptors. Finally, although SIA seemed to be a unitary phenomenon, the present results strengthened the idea that SIA is induced by exposure to forced walking stress with characteristics dependent on the duration of exposure.

Topics: Animals; Formaldehyde; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, Opioid; Stress, Physiological; Walking

We previously reported that the morphine-induced place preference was attenuated under inflammation produced by the unilateral injection of 2.5 % formalin (50 microl) into the hind paw of rats. In the present study, to elucidate the mechanism of this attenuation, the effects of pretreatment with delta- and kappa-opioid receptor antagonists, naltrindole (NTI) and nor-binaltorphimine (nor-BNI), on the development of the morphine-induced place preference under inflammation were examined in rats. Nor-BNI, but not NTI, eliminated the suppression of the morphine-induced place preference in inflamed groups. These results suggest that endogenous kappa-opioid systems may be activated in the presence of chronic inflammatory nociception; as a result, the development of morphine's rewarding effect may be suppressed under inflammation.

Topics: Animals; Chronic Disease; Conditioning, Psychological; Formaldehyde; Hindlimb; Inflammation; Male; Morphine; Naltrexone; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Reward; Time Factors

The analgesia-producing mechanism of processed Aconiti tuber was examined using rodents whose nociceptive threshold was decreased by loading repeated cold stress (RCS). The antinociceptive effect of processed Aconiti tuber (0.3 g/kg, p.o.) in RCS-loaded mice was antagonized by pretreatment with a kappa-opioid antagonist, nor-binaltorphimine (10 mg/kg, s.c.), and was abolished by an intrathecal injection of anti-dynorphin antiserum (5 microg). The Aconiti tuber-induced antinociception was inhibited by both dexamethasone (0.4 mg/kg, i.p.) and a dopamine D2 antagonist, sulpiride (10 mg/kg, i.p.), in RCS-loaded mice, and it was eliminated by both an electric lesion of the hypothalamic arcuate nucleus (HARN) and a highly selective dopamine D2 antagonist, eticlopride (0.05 microg), administered into the HARN in RCS-loaded rats. These results suggest that the analgesic effect of processed Aconiti tuber was produced via the stimulation of kappa-opioid receptors by dynorphin released in the spinal cord. It was also shown that dopamine D2 receptors in the HARN were involved in the expression of the analgesic activity of processed Aconiti tuber.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Administration, Topical; Analgesics; Animals; Arcuate Nucleus of Hypothalamus; Cold Temperature; Dexamethasone; Dopamine Antagonists; Drugs, Chinese Herbal; Dynorphins; Glucocorticoids; Hypothalamus; Immune Sera; Ligands; Male; Mice; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Salicylamides; Spinal Cord; Sulpiride

1DMe, a neuropeptide FF (NPFF) analogue, has been shown to produce antinociception and to enhance morphine analgesia in rats after intrathecal administration. To determine whether 1DMe could correct hyperalgesia and restore morphine efficacy in mononeuropathic (MN) and diabetic (D) rats we examined the spinal effect of 1DMe in MN and D rats without and after spinal blockade of mu- and delta-opioid receptors with CTOP and naltrindole, respectively. The influence of 1DMe on morphine-induced antinociception was assessed in the two models using isobolographic analysis. Whereas 1DMe intrathecally injected (0.1, 1, 7.5 microg rat(-1)) was ineffective in normal (N) rats, it suppressed mechanical hyperalgesia (decrease in paw pressure-induced vocalisation thresholds) in both MN and D rats. This effect was completely cancelled by CTOP (10 microg rat(-1)) and naltrindole (1 microg rat(-1)) suggesting that it requires the simultaneous availability of mu- and delta-opioid receptors. The combinations of morphine: 1DMe (80.6:19.4% and 99.8:0.2%, in MN and D rats, respectively) followed by isobolographic analysis, showed a superadditive interaction, relative to the antinociceptive effect of single doses, in D rats only. In N rats, the combination of morphine: 1DMe (0.5 mg kg(-1), i.v.: 1 microg rat(-1), i.t., ineffective doses) resulted in a weak short-lasting antinociceptive effect. These results show a different efficacy of 1DMe according to the pain model used, suggesting that the pro-opioid effects of the NPFF in neuropathic pain are only weak, which should contribute to hyperalgesia and to the impaired efficacy of morphine.

Topics: Analgesia; Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hyperalgesia; Injections, Spinal; Male; Morphine; Naltrexone; Narcotic Antagonists; Nervous System Diseases; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Somatostatin; Time Factors; Vocalization, Animal

We investigated the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl] pyrazole, in the tail-pinch test in mice, and evaluated the mechanism of action using various opioid receptor antagonists. P.o. and i.t. injection of FR140423 exerted dose-dependent antinociceptive activities with ED50 values of 21 mg/kg and 3.1 microg/mouse, respectively. However, i.c.v. injection of FR140423 did not show an antinociceptive effect. The antinociceptive effects of FR140423 were completely abolished by naloxone and naltrindole but not by naloxonazine, beta-funaltrexamine and nor-binaltorphimine. FR140423 did not affect any opioid receptor binding in mouse spinal membranes at concentrations up to 100 microM in vitro. Naloxone-induced jumping and diarrhea tests for morphine-like physical dependence of FR140423 gave negative results. These results suggest that FR140423 can induce antinociception by acting on the spinal but not the supraspinal site, and that spinal delta-opioid systems indirectly play a role in the antinociception produced by FR140423 in mice.

Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Binding, Competitive; Diarrhea; Injections, Intraventricular; Injections, Spinal; Male; Membranes; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Pyrazoles; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord; Sulfoxides

The effects of a daily injection of the delta selective opioid antagonist naltrindole (1 mg/kg), from birth to postnatal day 19, on antinociceptive responses to morphine (2 mg/kg) in 20-day-old rats of both sexes were investigated. The effects of postnatal handling were studied by including two control groups--one group receiving daily injections of saline, and a naive unhandled group. Antinociception was assessed using the tail-immersion test and time-response curves (5, 10, 15, and 30 min) were carried out for all experimental groups. In all treatment groups females showed greater sensitivity to the noxious stimuli compared to males. No significant effect of naltrindole treatment on baseline latencies was found. Postnatal handling increased sensitivity to thermal pain in both sexes, and reduced the effect of morphine in males. No significant effect of chronic naltrindole administration on morphine antinociception was found in this sex. Naltrindole-treated females showed an increased antinociception when compared to unhandled animals of the same gender. The results indicate that preweanling handling stress and chronic naltrindole treatment differentially affected morphine antinociception in male and female neonatal rats.

Topics: Analgesics; Animals; Female; Handling, Psychological; Male; Morphine; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Sex Characteristics; Stress, Physiological

We have previously reported that ischemic spinal cord injury in rats leads to chronic pain-related behaviors. Thus, rats exhibited aversive reactions to innocuous mechanical stimuli (mechanical allodynia) applied to a body area at or rostral to the dermatomes innervated by the injured spinal segments. The responses of the rats to cold are also markedly enhanced (cold allodynia). Interestingly, more than 50% of spinally injured rats did not develop these abnormal pain-related behaviors after spinal cord injury. In the present study, we showed that the extent of injury is similar between allodynic and non-allodynic rats. Furthermore, intrathecal (i.t.) naloxone, a broad-spectrum opioid receptor antagonist, reversibly provoked mechanical and cold allodynia-like responses in spinally injured rats that did not develop such behaviors spontaneously. However, naloxone did not elicit such reactions in normal rats and did not alter the tail-flick latency in normal or spinally injured rats. Furthermore, i.t. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) or naltridole, selective antagonists of mu and delta opioid receptors, respectively, also triggered pain-related behaviors similarly to naloxone. Although norbinaltorphimine (nor-BIN), a selective kappa-receptor antagonist, also elicited such responses, the time course of the effect makes it unlikely that spinal kappa-receptors were involved. These results suggested that the expression of abnormal pain-related behaviors in some spinally injured rats is tonically suppressed by the spinal opioidergic system. Interindividual differences that lead to lack or dysfunction of such inhibition may underly the appearence of pain-related behavior in some, but not all, spinally injured rats. It is suggested that such inhibition is exerted through spinal mu and delta, but not kappa, opioid receptors. The endogenous opioidergic control appears to be only active against abnormal painrelated behaviors in spinally injured rats. Our results are relevant for the clinical observation that only a subgroup of patients with nerve injury suffers from neuropathic pain.

Topics: Animals; Behavior, Animal; Chronic Disease; Cold Temperature; Female; Hyperalgesia; Injections, Spinal; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Self Mutilation; Somatostatin; Spinal Cord Injuries; Stress, Mechanical

The present study was performed to explore the modulatory potential of different endogenous opioid systems on transmission of presumed nociceptive information at the spinal cord level in thermally injured rats. Thermal injury was performed by dipping the left paw into water 60 degrees C for 20 s. This induced a significant bilateral decrease in hindpaw withdrawal latency HWL to pressure. Intrathecal administration of 10 nmol of CGRP8-37 induced a significant bilateral increase in HWL in the thermally injured group and in the intact controls. The effect of different opioid receptor antagonists on the increased latency to withdrawal response induced by intrathecal injection of 10 nmol of CGRP8-37 was explored in the thermally injured rats. The effect was reversed by intrathecal injection of 40 and 80 nmol of: b-funaltrexamine (mu opioid receptor antagonist) and naltrindole (delta opioid receptor antagonist), but not by norbinaltorphimine (kappa opioid receptor antagonist). The results of the present study show that intrathecal CGRP8-37 increases hindpaw withdrawal latency in thermally injured rats, an effect reduced by a mu as well as by a delta opioid receptor antagonist.

Topics: Animals; Brain Chemistry; Burns; Calcitonin Gene-Related Peptide; Hindlimb; Injections, Spinal; Male; Mitogens; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Peptide Fragments; Pressure; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reflex

The effect of a daily injection of the delta-selective opioid antagonist naltrindole (1 mg/kg), from birth to postnatal day 19, on the development of stress-induced-antinociception (SIA) and on the antinociceptive response to the mu-selective agonist alfentanil (65 microg/kg) in female rats was investigated. Functional blockade of the delta-receptor during the preweanling period markedly reduced the antinociceptive response to swim-stress in 25-day-old rats, and SIA was only mediated by delta-receptors at this age. In 20-day-old rats and in adults, SIA was predominantly mu-receptor mediated and unaffected by delta-receptor blockade. The lack of interference with mu-receptor function was confirmed as alfentanil responses were unaffected by preweanling naltrindole treatment. The data show independence of mu- and delta-receptors in the control of SIA during development and an impairment of delta- but not mu-mediated SIA after chronic delta-antagonist treatment.

Topics: Aging; Alfentanil; Analgesics, Opioid; Animals; Animals, Newborn; Drug Administration Schedule; Female; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Stress, Psychological; Swimming

The antinociceptive effect of intrathecally (i.t.) administered protease inhibitors was tested against capsaicin (800 ng) injected into the dorsal surface of a hindpaw. Both p-hydroxymercuribenzoate (2-8 nmol), a cysteine protease inhibitor, and phosphoramidon (1-4 nmol), an endopeptidase 24.11 inhibitor in the presence of bestatin (0.25 nmol) an aminopeptidase inhibitor, administered i.t. 60 min prior to the injection of capsaicin produced a dose-dependent reduction of the capsaicin-induced paw licking and biting response. p-Hydroxymercuribenzoate (4 nmol)-induced antinociception was significantly antagonized by nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-opioid receptor antagonist. On the other hand, phosphoramidon (4 nmol) /bestatin-induced antinociception was significantly antagonized by naltrindole, but not by nor-binaltorphimine. The results indicate that the antinociceptive effect of p-hydroxymercuribenzoate may be due to the inhibition of a cysteine protease degrading endogenous dynorphins whereas phosphoramidon in the presence of bestatin blocks the degradation of enkephalins.

Topics: Animals; Capsaicin; Dose-Response Relationship, Drug; Drug Combinations; Glycopeptides; Hindlimb; Hydroxymercuribenzoates; Injections, Spinal; Leucine; Male; Mice; Mice, Inbred Strains; Naltrexone; Narcotic Antagonists; Pain; Protease Inhibitors; Receptors, Opioid; Time Factors

CD-1 mice were treated intravenously with streptozotocin, 200 mg/kg, and tested 2 weeks later or treated with 60 mg/kg and tested 3 days later. Both treatments changed the tail flick response of heroin and 6-monoacetylmorphine (6 MAM) given intracerebroventricularly from a mu- to delta-opioid receptor-mediated action as determined by differential effects of opioid receptor antagonists. The response to morphine remained mu. Heroin and 6 MAM responses involved delta1 (inhibited by 7-benzylidenenaltrexone) and delta2 (inhibited by naltriben) receptors, respectively. These delta-agonist actions did not synergize with the mu-agonist action of morphine in the diabetic mice. The expected synergism between the delta agonist, [D-Pen2-D-Pen5]enkephalin (DPDPE), and morphine was not obtained in diabetic mice. Thus, diabetes disrupted the purported mu/delta-coupled response. In nondiabetic CD-1 mice, heroin and 6 MAM produced a different mu-receptor response (not inhibited by naloxonazine) from that of morphine (inhibited by naloxonazine). Also, these mu actions, unlike that of morphine, did not synergize with DPDPE. The unique receptor actions and changes produced by streptozotocin suggest that extrinsic in addition to genetic factors influence the opioid receptor selectivity of heroin and 6 MAM.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Benzylidene Compounds; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heroin; Injections, Intraventricular; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu; Streptozocin; Time Factors

The intra-third-ventricular (i.t.v.) administration of [Met5]-enkephalin (enk) to rats pretreated i.t.v. with three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon, inhibited the tail-flick response. The enk-induced inhibition was augmented by increasing the doses of the three PIs, with the maximum inhibition being attained at the doses of 10 nmol each. The enk-induced inhibition in rats pretreated with any combination of two PIs, however, were markedly smaller than that in rats pretreated with all three PIs, indicating that three kinds of enzymes all played important roles in the inactivation of enk. The inhibitory effect of enk on the tail-flick response in rats pretreated with the three PIs at doses of 10 nmol each was approximately tenfold higher than that of morphine. The relative anti-nociceptive potencies of enk and morphine were similar to the relative inhibitory potencies obtained previously with the isolated guinea pig ileum pretreated with the three PIs, indicating that the hydrolysis of the i.t.v. administered enk was largely prevented by the three PIs. However, the magnitude of the enk-induced inhibition in rats pretreated s.c. with the three PIs indicated that the hydrolysis of enk injected i.t.v. was not largely prevented by the s.c. administration of three PIs at doses up to 10 micromol each/kg.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Captopril; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enkephalin, Methionine; Glycopeptides; Injections, Intraventricular; Injections, Subcutaneous; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Peptides; Protease Inhibitors; Rats; Rats, Wistar

The role of neuropeptide FF (NPFF) in the modulation of spinal nociception was studied in rats with carrageenan inflammation in the hind paw. Normally no NPFF-ir neuronal cell bodies are found in the spinal cord. During inflammation NPFF-neurons were seen in an area receiving innervation from the inflamed hind limb, but in rats pretreated with morphine no NPFF-ir neurons were found. NPFF or IgG from NPFF immunoserum administered intrathecally had no effect in thermal and mechanical nociceptive tests. Morphine produced significant antinociception in both tests in the inflamed paw, but the effect was not modified by NPFF. These findings differ from the effects of intrathecal administration of NPFF and opioids in acute thermal tests when no inflammation is present. The role of NPFF in the modulation of nociception in the spinal cord may be markedly changed during acute inflammation.

Topics: Animals; Carrageenan; Hot Temperature; Inflammation; Male; Morphine; Naltrexone; Narcotic Antagonists; Neurons; Neuropeptides; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord

Physiological as well as hormone-simulated pregnancy (HSP) is associated with opioid-mediated elevations in maternal nociceptive thresholds. Previous reports from this laboratory have demonstrated the involvement of spinal cord kappa opiate receptors in this phenomenon. The present study was undertaken in order to determine the exclusivity of this mediation. Intrathecal (i.t.) administration of the delta opiate receptor-selective antagonists naltrindole (NTI), 7-benzylidenenaltrexone (BNTX) or naltriben (NTB) substantially reduces nociceptive thresholds of gestation (day 20) and HSP (day 19). Hyperalgesic actions of these compounds following i.t. administration are not observed in non-pregnant or vehicle-treated control animals. These data indicate that delta opiate receptor activity is a prerequisite for the manifestation of a substantial portion of gestational and HSP analgesia. In contrast, i.t. application of the micro-selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) has no effect on nociceptive thresholds of gestational day 20, as was previously demonstrated for HSP-induced antinociception. Thus, the potent spinal mu analgesic system does not participate in gestational or HSP analgesia. During physiological pregnancy, less robust constituents of intrinsic opioid pain-attenuating systems in the spinal cord (delta and kappa opioid systems) are recruited to mediate the maternal antinociception of gestation. Furthermore, the ability of estrogen and progesterone to modulate spinal opioid antinociceptive activity emphasizes potential differences between men and women in their response to pain medication.

Topics: Animals; Benzylidene Compounds; Female; Humans; Injections, Spinal; Male; Naltrexone; Narcotic Antagonists; Pain; Pregnancy; Pregnancy, Animal; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Sensory Thresholds; Sex Characteristics; Spinal Cord; Time Factors

The present experiments explored the role of endogenous opioids in the behavioral response to a formalin-induced nociceptive stimulus in the rat. Flinching was taken as a measure of the intensity of the nociceptive stimulus after the administration of formalin into the dorsal surface of the paw of control animals, or in animals receiving i.p. administration of receptor-selective doses of opioid antagonists including naloxone, naltrindole (delta opioid antagonist), nor-binaltorphimine (kappa opioid antagonist) or beta-funaltrexamine (mu opioid antagonist). Additionally, antisera to [Leu5]enkephalin, [Met5]enkephalin and dynorphin A (1-13) (dynorphin) were administered intrathecally before formalin to explore the contribution of endogenous opioids in modulation of the flinching response. Formalin-induced flinching was increased significantly by naloxone, and receptor selective doses of naltrindole and nor-binaltorphimine, but not beta-funaltrexamine. Additionally, antisera to [Leu5]enkephalin and dynorphin also resulted in a significant increase in formalin-induced flinching, whereas antisera to [Met5]enkephalin had no effect. On the basis of significant increases in formalin-induced flinching produced by 1) receptor-selective doses of delta and kappa, but not mu, opioid antagonists and 2) antisera to [Leu5]enkephalin and dynorphin A, but not [Met5]enkephalin, these data suggest the presence of an opioid inhibitory tone which acts to limit the intensity of the pain signal. This tone appears to be mediated via activation of delta and kappa receptors, possibly by a [Leu5]enkephalin- and dynorphin-like substance, respectively.

Topics: Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Formaldehyde; Immune Sera; Male; Naloxone; Naltrexone; Narcotic Antagonists; Opioid Peptides; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa

Cholecystokinin (CCK) may act as an endogenous anti-opioid and blockade of CCK receptors can enhance the potency and efficacy of morphine. This effect is blocked by opioid delta (delta) receptor antagonists, suggesting a tonic inhibitory action of CCK to diminish the release and/or availability of endogenous enkephalins. The present studies have further evaluated this possibility by studying the antiallodynic actions of a CCKB antagonist (L365,260) alone, or in the presence of thiorphan (a neutral endopeptidase inhibitor) in a model of peripheral neuropathy. Animals subjected to nerve injury, but not sham controls, exhibited long lasting, stable mechanical allodynia. Intrathecal (i.t.) administration of L365,260 or thiorphan alone did not alter allodynia. However, co-administration of these compounds produced a significant antiallodynic action which was antagonized by receptor selective doses of naltrindole, an opioid delta receptor antagonist. In addition, antisera to [Leu5]enkephalin, but not to [Met5]enkephalin, also blocked the antiallodynic action of thiorphan plus L365,260. These data suggest that blockade of CCKB receptors may enhance the actions or availability of endogenous [Leu5]enkephalin or a like substance which can elicit a significant antiallodynic action via opioid delta receptors when its degradation is by inhibited by thiorphan. The data suggest that delta opioids are involved in regulation of some aspects of nerve-injury induced pain.

Topics: Animals; Male; Naltrexone; Narcotic Antagonists; Pain; Peripheral Nervous System; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Thiorphan

The present study was undertaken to investigate the effects of the opioid peptide Met-enkephalin (met-enk) on the release of substance P-like immunoreactivity (SPLI) in the lumbar dorsal horn during the application of a noxious mechanical or thermal stimulus to the ipsilateral hind paw and lower limb of the rat. A push-pull cannula was introduced to the lumbar dorsal horn in non-anesthetized decerebrate/spinal transected rats. The dorsal horn was perfused with artificial CSF and the collected perfusates were assayed for SPLI using radioimmunoassay. A noxious mechanical or thermal stimulus was applied to different areas of the ipsilateral hind paw and lower limb. Met-enk (500 nM) applied to the dorsal horn through the perfusate reduced the basal release of SPLI by 29 +/- 9% and prevented the increase in the release of SPLI evoked by the noxious mechanical or thermal stimulus. The effect of met-enk was blocked by the selective delta-opioid receptor antagonist naltrindole (500 nM). Naltrindole (NTD) alone elicited a 75 +/- 30% increase in the basal release of SPLI. These data show that met-enk inhibits the thermally or mechanically evoked release of SPLI in the dorsal horn by activating the delta opioid receptors. These receptors are also involved in the tonic spinal regulation of the release of SPLI.

Topics: Animals; Decerebrate State; Enkephalin, Methionine; Functional Laterality; Hindlimb; Hot Temperature; Male; Naltrexone; Narcotic Antagonists; Pain; Physical Stimulation; Rats; Rats, Wistar; Receptors, Opioid, delta; Spinal Cord; Substance P; Time Factors

Neuropeptide FF (NPFF) has been found to act as an antiopioid peptide. However, IT NPFF has recently been shown to potentiate the antinociceptive effects of IT morphine and to produce antinociception on its own. The aim of this study was to find out whether pretreatment with NPFF causes a comparable potentiation of dexmedetomidine-induced antinociception. NPFF (0.05-10.0 nmol) produced no antinociceptive effects in the rat tail flick test. NPFF potentiated the antinociceptive effect of IT morphine (7.8 nmol). This potentiation was prevented by IT naltrindole (28 nmol), which did not attenuate the antinociceptive effect of morphine. Dexmedetomidine (1.6-6.4 nmol) produced a dose-dependent antinociceptive effect, which was not potentiated by NPFF. Activation of the endogenous delta-opioid system due to the antiopioid effect of IT NPFF is proposed as an explanation to the reported differential action of NPFF on the mu-opioid and the alpha 2-adrenergic systems.

Topics: Adrenergic alpha-Agonists; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Synergism; Imidazoles; Male; Medetomidine; Morphine; Naltrexone; Narcotic Antagonists; Neuropeptides; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Receptors, Opioid, mu; Spinal Cord; Time Factors

The mechanisms of the antinociceptive effect of mexiletine were assessed by administering selective mu-, delta- and kappa-opioid receptor antagonists in diabetic and non-diabetic mice. Intraperitoneal administration of mexiletine, at doses of 10 and 30 mg/kg, produced dose-dependent antinociception in the tail-pinch test in both non-diabetic and diabetic mice. The antinociceptive effect of mexiletine in diabetic mice was significantly greater than that in non-diabetic mice. The antinociceptive effect of mexiletine did not result from the activation of mu- or kappa-opioid receptors in either non-diabetic or diabetic mice, since treatment with either beta-funaltrexamine, a selective mu- opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist, was ineffective in blocking mexiletine-induced antinociception. The antinociceptive effect of mexiletine was significantly antagonized by naltrindole, a selective delta-opioid receptor antagonist, in both non-diabetic and diabetic mice. Furthermore, the antinociceptive effect of mexiletine was significantly reduced in both non-diabetic and diabetic mice following pretreatment with 7-benzylidenenaltrexone, a selective delta 1-opioid receptor antagonist, but not with naltriben, a selective delta 2-opioid receptor antagonist. These result suggest that delta 1-opioid receptor-mediated mechanisms may be involved in the antinociceptive effect of mexiletine.

Topics: Animals; Diabetic Neuropathies; Male; Mexiletine; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reference Values

Substance P, a putative neurotransmitter or neuromodulator of nociception or pain in the spinal cord, exhibits both antinociceptive and hyperalgesic properties. Investigators have shown that the N-terminal metabolite of substance P, substance P(1-7), produces naloxone-reversible antinociception when given supraspinally and systemically in mice and hyperalgesia when injected intrathecally in rats. The goal of our investigation was to identify the receptors mediating these actions of substance P(1-7) at the initial site of release of substance P, i.e. in the spinal cord. Thirty minutes after intrathecal injection, substance P(1-7) produced naloxone-reversible antinociception in a dose-dependent manner in the abdominal stretch assay. When administered with naloxone, substance P(1-7) produced hyperalgesia 5 and 10 min after injection, which was inhibited by dizocilpine (MK-801), a phencyclidine ligand and non-competitive antagonist of N-methyl-D-aspartate. Antinociception was inhibited by the mu-selective opioid antagonist beta-funaltrexamine, but not by the mu 1-selective opioid antagonist naloxonazine or the delta-selective antagonist naltrindole, indicating a mu 2-opioid receptor-mediated effect. These findings suggest that the N-terminal portion of substance P may modulate nociception or pain, as demonstrated in the acetic acid abdominal stretch (writhing) assay, via activation of two different receptor systems. Substance P(1-7)-induced hyperalgesia is mediated by a phencyclidine-sensitive mechanism and antinociception involves activity at mu-opioid, most likely mu 2, receptors.

Topics: Animals; Biological Assay; Disease Models, Animal; Dizocilpine Maleate; Hyperalgesia; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Peptide Fragments; Phencyclidine; Receptors, Opioid, mu; Spinal Cord; Substance P

The prevailing view is that supraspinal mu opioid-mediated antinociception in mice is mediated via the mu 1 subtype. The purpose of the present study was to determine if the highly mu-selective compound etonitazene could produce supraspinal (intracerebroventricular; i.c.v.) antinociception in CXBK mice, which are deficient in brain mu1, but not mu2, opioid receptors. CXBK or normal Crl:CD-1 (ICR)BR mice were administered graded doses of etonitazene i.c.v. and 15 min later antinociception was assessed by a standard radiant-heat or 55 degrees C water tail-flick test. Etonitazene produced dose-related antinociception that was blocked by naloxone and by beta-FNA (demonstrating a mu opioid mechanism), but not by either ICI-174,864 or naltrindole (demonstrating the lack of involvement of delta opioid receptors). These findings suggest that mu2 opioid receptors are important contributors to opioid-induced supraspinal antinociception in mice.

Topics: Animals; Benzimidazoles; Cerebral Ventricles; Dose-Response Relationship, Drug; Enkephalin, Leucine; Hot Temperature; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Mice, Mutant Strains; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, mu; Spinal Cord

Intravenous (i.v.) administration of morphine produces a dose-dependent inhibition of the tail-flick (TF) reflex, depressor response, and bradycardia in the rat. Some of these effects depend on interactions of i.v. morphine with peripheral opioid receptors and the integrity of cervical vagal afferents. The present studies used the relatively specific mu, delta, and kappa opioid receptor agonists (DAGO, DPDPE or U-50,488H) and the relatively specific mu, delta, and kappa opioid receptor antagonists (beta-FNA, naloxonazine, naltrindole or nor-BNI) in either intact rats or rats with bilateral cervical vagotomy (CVAG) to delineate the vagal afferent/opioid-mediated components of these effects. I.v. administration of DAGO in intact rats produced a dose-dependent inhibition of the TF reflex, depressor response, and bradycardia virtually identical to those produced by i.v. morphine. All of these effects of either i.v. DAGO or i.v. morphine were significantly attenuated by either bilateral CVAG or pre-treatment with the mu 2 opioid receptor antagonist beta-FNA. Pre-treatment with the mu 1 opioid receptor antagonist naloxonazine affected i.v. DAGO-induced inhibition of the TF reflex and bradycardia, but had no significant effects on i.v. morphine-produced responses. I.v. administration of DPDPE produced a dose-dependent pressor response, but had no marked effects on the either the TF reflex or heart rate (HR). The pressor response was unaffected by either bilateral CVAG or pre-treatment with naltrindole, naloxone, hexamethonium, or bertylium. i.v. administration of U-50,488H produced a depressor response and bradycardia, but had no significant effect on the TF reflex. The depressor response and bradycardia produced by i.v. U-50,488H were unaffected by bilateral CVAG, but could be antagonized by pre-treatment with either nor-BNI or naloxone. These studies suggest that the vagal afferent-mediated antinociceptive and cardiovascular effects of i.v. morphine are primarily mediated by interactions with low affinity mu 2 opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analysis of Variance; Animals; Blood Pressure; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heart Rate; Hexamethonium; Hexamethonium Compounds; Indoles; Injections, Intravenous; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors; Vagotomy; Vagus Nerve

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Arthritis; Benzomorphans; Dose-Response Relationship, Drug; Injections, Intravenous; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Vocalization, Animal

We examined whether streptozotocin-induced diabetes can modulate beta-endorphin-induced antinociception in mice. While beta-endorphin administered i.c.v. produced a dose-dependent inhibition of the tail-flick response in both diabetic and non-diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The ED50 value of beta-endorphin administered i.c.v. in diabetic mice was significantly lower than that in non-diabetic mice. The antinociceptive effects of beta-endorphin administered i.c.v. in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective delta-opioid receptor antagonist. beta-Endorphin administered i.t. also produced a dose-dependent antinociception in both diabetic and non-diabetic mice. However, the ED50 value of kappa-opioid receptor antagonist. On the other hand, the antinociceptive potency of DPDPE, a selective delta-opioid agonist, administered i.t. is significantly increased in diabetic mice, as compared with non-diabetic mice, whereas, the antinociceptive potency of U-50,488H, a kappa-opioid receptor agonist, administered i.t. is significantly less than in non-diabetic mice. These results suggest that diabetes may modulate beta-endorphin-induced antinociception differently at the spinal and supraspinal levels.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; beta-Endorphin; Cerebral Ventricles; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Pain; Pyrrolidines; Reference Values

The effect of various doses of the selective delta agonist BUBU (Tyr-D-Ser(O-t-butyl)-Gly-Phe-Leu-Thr(O-t-butyl) on the vocalization threshold to paw pressure were compared in normal and arthritic rats, a suitable clinical model of chronic pain. In both group of rats, the intravenous administration of BUBU (6, 9, 12 mg/kg in normal and 1.5, 3, 6 mg/kg in arthritic rats) led to significant antinociceptive effects. The same dose of BUBU (6 mg/kg i.v.) produced a much more potent antinociceptive effect in arthritic than in normal rats, and a dose as low as 1.5 mg/kg produced a significant analgesic effect in the arthritic animal, whereas at 3 mg/kg BUBU was ineffective in normal rats. The analgesic effects of BUBU (9 mg/kg in normal and 3 mg/kg in arthritic rats) were completely prevented by the selective delta antagonist naltrindole (1 mg/kg i.v. a dose devoid of analgesic potency per se), while they were not affected by the selective mu antagonist naloxone (0.05 mg/kg i.v.). In addition, 3 mg/kg i.v. of BUBU remained effective in morphine tolerant arthritic rats. These results suggest that delta opioid receptor activation can modulate the transmission of cutaneous mechanical nociceptive information in rats, especially in inflammatory pain conditions.

Topics: Analgesics; Animals; Arthritis, Experimental; Drug Administration Schedule; Drug Interactions; Enkephalins; Male; Morphine; Naloxone; Naltrexone; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Reference Values; Vocalization, Animal

We have studied the effects of several opioid antagonists on a type of footshock stress-induced analgesia (FSIA) measured by the tail-flick test in male mice. Naloxone injected either subcutaneously (0.1-10 mg/kg) or intrathecally (1-20 micrograms) antagonized FSIA at higher doses than those that blocked a similar degree of analgesia induced by morphine. Intracerebroventricular (i.c.v.) naloxone (1-20 micrograms) did not modify the FSIA while antagonizing the i.c.v. morphine-induced analgesia. As a consequence, the antagonism of the FSIA by naloxone probably occurs at the level of the spinal cord and through receptors different than mu. The delta selective antagonist naltrindole (0.1-3 mg/kg s.c.) did not antagonize the analgesic effects of the stress. Nor-binaltorphimine, a kappa selective antagonist, blocked the FSIA when administered systemically (1-4 mg/kg i.p.) or locally (0.1-1 microgram i.t.). These results strongly suggest that spinal kappa opioid receptors are responsible for this type of endogenous analgesia.

Topics: Analgesia; Animals; Cerebral Ventricles; Electroshock; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, kappa; Spinal Cord; Stress, Psychological

This study evaluated the antinociceptive effects of systemically administered selective opioid agonists of mu (DAMGO), delta (BUBU) and kappa (U 69593) receptors on the vocalization threshold to paw pressure in a rat model of peripheral unilateral mononeuropathy produced by loose ligatures around the common sciatic nerve. DAMGO (0.5-2 mg/kg), BUBU (1.5-6 mg/kg) and U 69593 (0.75-3 mg/kg) injected intravenously (i.v.) produced a potent long-lasting antinociceptive effect on both hind paws. The effects on the lesioned paw were clearly and statistically more potent than for the non-lesioned paw. The selective antinociceptive effect of 2 mg/kg DAMGO, 3 mg/kg BUBU and 1.5 mg/kg U 69593 were completely prevented by prior administration of the appropriate antagonists: 0.1 mg/kg naloxone, 1 mg/kg naltrindole and 0.4 mg/kg MR 2266. The present data clearly show that an acute i.v. injection of these selective opioid agonists induces potent antinociceptive effects in a rat model of peripheral neuropathy. These data are discussed with regard to the classical view that there is opioid resistance in neuropathic pain.

Topics: Analgesics; Animals; Benzeneacetamides; Benzomorphans; Disease Models, Animal; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vocalization, Animal

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The preceding companion paper and the present work were aimed at identifying the neuroanatomical loci at which opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 8 experiments included in the present paper examined the effect of microinjecting either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist) either into the third ventricle or over the frontal cortex. Taken together, these experiments demonstrate that the late (80-100 shock) opiate analgesia is mediated by delta opiate receptors located within subcortical structures rostral to the 4th ventricle. No evidence for supraspinal opiate involvement in the early (2 shock) opiate analgesia was found.

Topics: Analysis of Variance; Animals; Cerebral Ventricles; Dose-Response Relationship, Drug; Electroshock; Indoles; Injections, Intraventricular; Injections, Spinal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Spinal Cord

When administered repeatedly, in conjunction with hot plate testing, naloxone and naltrexone have the paradoxical effect of producing antinociception in rats and mice. Recently, we have found that the sub-acute selective blockade of mu opioid receptors leads to the development of antinociception and an augmentation of kappa receptor-mediated antinociception. In this study, acute delta/kappa antagonist treatment produced a significant decrease in paw lick latency in rats displaying antinociception induced by sub-acute mu blockade, however, the response level of these animals was still significantly above the baseline. In addition, rats receiving sub-acute combined mu and delta antagonist treatment took longer to develop an antinociceptive response than those treated with a mu antagonist alone. Sub-acute selective blockade of kappa or delta opioid receptors had no overall effect on paw lick latency during the course of 5 days of hot plate testing. The results indicate that delta receptor activity may play a role in the antinociception induced by sub-acute mu blockade. However, while delta antagonist treatment effected the expression, it did not completely attenuate the antinociception induced by sub-acute mu blockade suggesting that there is still a significant non-opioid component to this analgesic response. The results of a final experiment, in which acute delta antagonist treatment had no effect on antinociception induced by repeated systemic injections of naloxone, supported this hypothesis.

Topics: Animals; Indoles; Male; Morphinans; Naltrexone; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sensitivity and Specificity

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The present work and the following companion paper were aimed at identifying the neuroanatomical loci at which endogenous opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 3 experiments included in the present paper focus on the role of spinal opiates in tail-shock induced analgesia. The first experiment demonstrates that the tail-shock parameters used do not directly activate pain suppressive circuitry within the spinal cord, but rather activate centrifugal pain modulation circuitry originating within the brain. The last two experiments examine the effect of intrathecal microinjection of either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist). Taken together, these latter 2 experiments demonstrate that both the early (after 2 shocks) and late (after 80-100 shocks) opiate analgesias are mediated by kappa opiate receptors within the spinal cord.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Electroshock; Indoles; Injections, Spinal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Somatostatin; Spinal Cord

The modulatory effects of intrathecally (i.t.) administered dynorphin A(1-17) and dynorphin A(1-13) on morphine antinociception have been studied previously in rats by other investigators. However, both potentiating and attenuating effects have been reported. In this study, the modulatory effects of i.t. administered dynorphin A(1-17) as well as the smaller fragment, dynorphin A(1-8), were studied in mice. In addition, nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist, and naltrindole (NTI), a highly selective delta opioid receptor antagonist, were used to characterize the possible involvement of spinal kappa and delta opioid receptors in the modulatory effects of the dynorphins. Dynorphin A(1-17) and dynorphin A(1-8) administered i.t. at doses that did not alter tail-flick latencies, were both able to antagonize in a dose-dependent manner, the antinociceptive action of s.c. administered morphine sulfate. The antinociceptive ED50 of morphine sulfate was increased 3.9- and 5.3-fold by 0.4 nmol/mouse of dynorphin A(1-17) and dynorphin A(1-8), respectively. Injections of 0.4 and 0.8 nmol/mouse of nor-BNI i.t., but not its inactive enantiomer (+)-1-nor-BNI, inhibited dose-dependently the antagonistic effects of the dynorphins. These doses of nor-BNI alone did not affect the antinociceptive action of morphine sulfate. Intrathecal administration of 5 nmol/mouse of NTI also did not affect the modulatory effects of dynorphins. These observations that dynorphins exert their antagonistic effects on morphine-induced antinociception stereoselectively through spinal kappa opioid receptors may suggest a coupling between spinal kappa and mu opioid receptors.

Topics: Animals; Dynorphins; Indoles; Male; Mice; Morphinans; Morphine; Naltrexone; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Spine; Stereoisomerism

Until recently the only pharmacological probes for delta-receptors have been peptide enkephalin analogues. These suffer from a number of limitations including high cost, partial agonist effects and a propensity for neurotoxicity. A stable non-peptide antagonist, naltrindole, has recently become available. We have explored its intrinsic actions and found that it attenuated swim stress-induced antinociception, a model for endogenous delta-receptor activation. Naltrindole may therefore be a useful alternative to presently available delta-receptor antagonists.

Topics: Animals; Behavior, Animal; Indoles; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Stress, Psychological