beta-funaltrexamine and Pain

Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens (NAc) shell was observed after peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive-driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release, was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared with sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) μ-opioid receptors (MORs). The rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.

Topics: Adenocarcinoma; Analgesics, Opioid; Anesthetics, Local; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Bone Neoplasms; Cell Line, Tumor; Diclofenac; Disease Models, Animal; Female; Gyrus Cinguli; Lidocaine; Morphine; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Pain; Rats; Rats, Inbred F344

β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis. The present study investigated the contribution of peripheral cannabinoid (CB) and opioid systems in the antinociception produced by intraplantar (i.pl.) injection of BCP. The interaction between peripheral BCP and morphine was also examined.. The antinociceptive effect of i.pl. BCP was assayed by the capsaicin tests in mice. Antagonists for CB and opioid receptors, and antisera against β-endorphin were injected peripherally prior to i.pl. injection of BCP. Morphine in combination with BCP was injected subcutaneously or intrathecally.. The i.pl. injection of BCP dose-dependently attenuated capsaicin-induced nociceptive response. The antinociceptive effect produced by BCP was prevented by pretreatment with AM630, a selective CB2 receptor antagonist, but not by AM251, a selective CB1 receptor antagonist. Pretreatment with naloxone, an opioid receptor antagonist, and β-funaltrexamine, a selective μ-opioid receptor antagonist, reversed the antinociceptive effect of BCP. Pretreatment with naloxone methiodide, a peripherally acting antagonist for opioid receptors and antisera against β-endorphin, resulted in a significant antagonizing effect on BCP-induced antinociception. Morphine-induced antinociception was increased by a low dose of BCP. The increased effect of morphine in combination with BCP was antagonized significantly by pretreatment with naloxone.. The present results demonstrate that antinociception produced by i.pl. BCP is mediated by activation of CB2 receptors, which stimulates the local release from keratinocytes of the endogenous opioid β-endorphin. The combined injection of morphine and BCP may be an alternative in treating chemogenic pain.

Topics: Animals; Cannabinoids; Endorphins; Mice; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociception; Pain; Pain Measurement; Polycyclic Sesquiterpenes; Receptor, Cannabinoid, CB2; Sesquiterpenes

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

In our previous paper we reported synthesis and biological activity of two cyclic analogs of endomorphin-2 (EM-2): Tyr-c(Lys-Phe-Phe-Asp)-NH(2) and Tyr-c(Asp-Phe-Phe-Lys)-NH(2), achieved by making an amid bond between Lys and Asp side-chains. The first analog did not bind to the mu-opioid receptor, the affinity of the second one was very low. In the present study, we describe the synthesis of four novel cyclic analogs of similar structure, but with d-amino acids in position 2 (D-Lys or D-Asp). All new analogs displayed high affinity for the mu-opioid receptor, were much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) administration. Analgesic effect of the most potent cyclic analog, Tyr-c(D-Lys-Phe-Phe-Asp)NH(2) was much stronger and longer lasting than that of EM-2. This analog elicited analgesia also after peripheral administration and this effect was reversed by concomitant i.c.v. injection of the mu-opioid antagonist, beta-funaltrexamine, which indicated that antinociception was mediated by the mu-opioid receptor in the brain. Central action of the cyclic analog gives evidence that it was able to cross the blood-brain barrier, most likely due to the increased lipophilicity. Our results demonstrate that cyclization might be a promising strategy to enhance bioavailability of peptides and may serve a role in the development of novel endomorphin analogs with increased therapeutic potential.

Topics: Amino Acid Sequence; Analgesics, Opioid; Animals; Brain; Cell Membrane; Endorphins; Injections, Intravenous; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Peptides, Cyclic; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Tissue Extracts

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

We previously described a novel cyclic endomorphin-1 analog c[Tyr-D-Pro-D-Trp-Phe-Gly] (c[YpwFG]), acting as a mu-opioid receptor (MOR) agonist. This study reports that c[YpwFG] is more lipophilic and resistant to enzymatic hydrolysis than endomorphin-1 and produces preemptive antinociception in a mouse visceral pain model when injected intraperitoneally (i.p.) or subcutaneously (s.c.) before 0.6% acetic acid, employed to evoke abdominal writhing (i.p. ED(50)=1.24 mg/kg; s.c. ED(50)=2.13 mg/kg). This effect is reversed by the selective MOR antagonist β-funaltrexamine and by a high dose of the mu(1)-opioid receptor-selective antagonist naloxonazine. Conversely, the kappa-opioid receptor antagonist nor-binaltorphimine and the delta-opioid receptor antagonist naltrindole are ineffective. c[YpwFG] produces antinociception when injected i.p. after acetic acid (ED(50)=4.80 mg/kg), and only at a dose of 20mg/kg did it elicit a moderate antinociceptive response in the mouse, evaluated by the tail flick assay. Administration of a lower dose of c[YpwFG] (10mg/kg i.p.) apparently produces a considerable part of antinociception on acetic acid-induced writhes through peripheral opioid receptors as this action is fully prevented by i.p. naloxone methiodide, which does not readily cross the blood-brain barrier; whereas this opioid antagonist injected intracerebroventricularly (i.c.v.) is not effective. Antinociception produced by a higher dose of c[YpwFG] (20mg/kg i.p.) is partially reversed by naloxone methiodide i.c.v. administered. Thus, only at the dose of 20mg/kg c[YpwFG] can produce antinociception through both peripheral and central opioid receptors. In conclusion, c[YpwFG] displays sufficient metabolic stability to be effective after peripheral administration and demonstrates the therapeutic potential of endomorphin derivatives as novel analgesic agents to control visceral pain.

Topics: Analgesics; Animals; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Subcutaneous; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Peptides, Cyclic; Receptors, Opioid, mu

Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian tachykinin peptides encoded by the recently identified TAC4 gene in human, and the biological functions of these peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in pain modulation at the supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of h HK-1 (0.3, 1, 3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the NK(1) receptor antagonist SR140333, but not by the NK(2) receptor antagonist SR48968, indicating that the analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of NK(1) receptors. Interestingly, naloxone, beta-funaltrexamine and naloxonazine, but not naltrindole and nor-binaltorphimine, could also block the analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent analgesic effect after i.c.v. administration, however, the potency of analgesia was less than h HK-1. Surprisingly, SR140333 could not modify this analgesic effect, suggesting that this effect is not mediated through the NK(1) receptors like h HK-1. SR48968 could modestly enhance the analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to NK(2) receptors. Furthermore, none of the opioid receptor (OR) antagonists could markedly block the analgesia of h HK-1(4-11), suggesting that the analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta ORs significantly enhanced the analgesia, indicating that delta OR is a negatively modulatory factor in the analgesic effect of h HK-1(4-11). It is striking that bicuculline (a competitive antagonist at GABA(A) receptors) effectively blocked the analgesia induced by h HK-1(4-11), suggesting that this analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of pain.

Topics: Analgesics; Animals; Benzamides; Bicuculline; Dose-Response Relationship, Drug; GABA Antagonists; Humans; Injections, Intraventricular; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Peptide Fragments; Piperidines; Receptors, Neurokinin-2; Tachykinins; Tropanes

In the present study, we investigated whether the peripherally acting micro-opioid receptor agonist loperamide would inhibit allodynia in the non-inflamed dermatome of mice with herpetic pain. Subcutaneous (s.c.) injection of loperamide (1 and 3 mg/kg) inhibited allodynia. Local (intraplantar) injection of loperamide (1 and 5 microg/site) also produced an anti-allodynic effect. The peripheral opioid receptor antagonist naloxone methiodide (0.1 mg/kg, s.c.) and the micro-opioid receptor-selective antagonist beta-funaltrexamine (40 nmol/site, intraplantar and 20 mg /kg, s.c.) antagonized the anti-allodynic effects of systemic and local loperamide. Local injection of loperamide into the contralateral hind paw was without effect, suggesting that the effect is mediated through local action, not systemic action. Acute and subacute tolerance did not develop to the anti-allodynic effect of loperamide. In addition, there were no cross-tolerance between local opioids (morphine and loperamide) and systemic morphine. These results suggest that stimulation of peripheral micro-opioid receptors suppresses herpetic allodynia without tolerance development. The non-narcotic micro-opioid receptor agonist loperamide may relieve acute herpetic pain in patients with herpes zoster.

Topics: Analgesics, Opioid; Animals; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Tolerance; Female; Foot; Herpes Simplex; Herpesvirus 1, Human; Injections; Injections, Subcutaneous; Loperamide; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Physical Stimulation

We have previously shown that microinjection of galanin into the arcuate nucleus of hypothalamus (ARC) produced antinociceptive effects in rats (Sun et al., 2003a). In this study, the neural pathway of galanin from ARC to midbrain periaqueductal gray (PAG) in nociceptive modulation was investigated. The hindpaw withdrawal latencies (HWLs) with noxious thermal and mechanical stimulation were assessed by the hotplate and the Randall Selitto tests. Intra-ARC administration of 0.1, 0.5, or 1 nmol of galanin induced significant increases in HWLs of rats. The galanin-induced increases in HWLs were inhibited by injection of 10 microg of the opioid receptor antagonist naloxone or 1 nmol of the mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) into PAG, suggesting that the antinociceptive effects induced by intra-ARC injection of galanin occur via the neural pathway from ARC to PAG. Furthermore, our results demonstrate that the galaninergic fibers directly innervated the beta-endorphinergic neurons in ARC by immunofluorescent methods. Taken together, our results suggest that galanin produces antinociceptive effects in the ARC of rats by activating the beta-endorphinergic pathway from ARC to PAG.

Topics: Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Fluorescent Antibody Technique; Galanin; Hindlimb; Hot Temperature; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Neural Pathways; Neurons; Pain; Periaqueductal Gray; Physical Stimulation; Rats; Rats, Wistar

Previous studies have indicated that interferon-alpha (IFN-alpha) can bind to opioid receptors and exerts an antinociceptive effect in both peripheral and central nervous systems. The current study investigated the antinociceptive effect of IFN-alpha unilaterally microinjected into the thalamic nucleus submedius (Sm) of rats on noxious thermal stimulus, and the roles of different subtypes of opioid receptors in mediating the Sm IFN-alpha-evoked antinociception. The results indicated that unilateral microinjection of IFN-alpha (4, 8, 16 pmol) into the Sm dose-dependently increased the hind paw withdrawal latency from the noxious heat stimulus, and this effect was reversed by pretreatment with non-selective opioid receptor antagonist naloxone (200 pmol) and specific mu-opioid receptor antagonist beta-FNA (1 nmol) into the same sites, whereas delta-opioid receptor antagonist ICI174,864 (1 nmol) and kappa-opioid receptor antagonist nor-BNI (1 nmol) failed to alter the effect of IFN-alpha. These results suggest that Sm is involved in IFN-alpha-evoked antinociception and mu- but not delta- and kappa-opioid receptor mediates the Sm IFN-alpha-evoked antinociception.

Topics: Animals; Escape Reaction; Interferon-alpha; Male; Mediodorsal Thalamic Nucleus; Microinjections; Naloxone; Naltrexone; Pain; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, kappa; Receptors, Opioid, mu

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

We investigated the antinociceptive efficacy of systemic and centrally injected oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice. 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. Oral (p.o.) and i.t., but not i.c.v., administration of oxycodone prolonged the tail-flick latency in diabetic mice to a level that was considerably longer than the baseline latency in non-diabetic mice. However, morphine did not significantly inhibit the tail-flick response in diabetic mice. The antinociceptive effect of either p.o. or i.t. oxycodone in non-diabetic mice, but not in diabetic mice, was antagonized by pretreatment with a selective mu-opioid receptor antagonist, beta-funaltrexamine. In non-diabetic mice, pretreatment with a selective kappa-opioid receptor antagonist, nor-binaltorphimine, had no effect on the peak antinociceptive effect of either p.o. or i.t. oxycodone at 30 min after administration, however, it slightly but significantly reduced oxycodone-induced antinociception at 60 and 90 min after administration. On the other hand, pretreatment with nor-binaltorphimine practically abolished the antinociceptive effects of both p.o.- and i.t.-administered oxycodone in diabetic mice. Naltrindole, a selective delta-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in either non-diabetic or diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by spinal kappa-opioid receptors in diabetic mice, whereas it may interact primarily with supraspinal and spinal mu-opioid receptors in non-diabetic mice.

Topics: Analgesics, Opioid; Animals; Area Under Curve; Diabetes Mellitus, Experimental; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Streptozocin

Oxytocin has been implicated in the modulation of somatosensory transmission such as nociception and pain. The present study investigates the effect of oxytocin on formalin-induced pain response, a model of tonic continuous pain. The animals were injected with 0.1 ml of 1% formalin in the right hindpaw and the left hindpaw was injected with an equal volume of normal saline. The time spent by the animals licking or biting the injected paw during 0-5 min (early phase) and 20-25 min (late phase) was recorded separately. Oxytocin (25, 50, 100 microg/kg, i.p.) dose dependently decreased the licking/biting response, both in the early as well as the late phases. The antinociceptive effect of oxytocin (100 microg/kg, i.p.) was significantly attenuated in both the phases by a higher dose of the non-selective opioid receptor antagonist naloxone (5 mg/kg, i.p.), MR 2266 (0.1 mg/kg, i.p.), a selective kappa-opioid receptor antagonist and naltrindole (0.5 mg/kg, i.p.), a selective delta-opioid receptor antagonist but not by a lower dose of naloxone (1 mg/kg, i.p.) or beta-funaltrexamine (2.5 microg/mouse, i.c.v.), a selective mu-opioid receptor antagonist. Nimodipine, a calcium channel blocker (1 and 5 mg/kg, i.p.) produced a dose-dependent analgesic effect. The antinociceptive effect of oxytocin was significantly enhanced by the lower dose of nimodipine (1 mg/kg, i.p.) in both the phases. Chronic treatment with oxytocin (100 microg/kg/day, i.p. daily for 7 days) did not produce tolerance in both the phases of formalin-induced pain response. The results thus indicate that oxytocin displays an important analgesic response in formalin test; both kappa- and delta-opioid receptors as well as voltage-gated calcium channels seem to be involved in the oxytocin-induced antinociception.

Topics: Analgesics; Animals; Behavior; Calcium Channel Blockers; Dose-Response Relationship, Drug; Formaldehyde; Mice; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Nimodipine; Oxytocin; Pain; Random Allocation; Receptors, Opioid, delta; Receptors, Opioid, kappa

[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

7-hydroxymitragynine, a constituent of the Thai herbal medicine Mitragyna speciosa, has been found to have a potent opioid antinociceptive effect. In the present study, we investigated the mechanism of antinociception and the inhibitory effect on gastrointestinal transit of 7-hydroxymitragynine, and compared its effects with those of morphine. When administered subcutaneously to mice, 7-hydroxymitragynine produced antinociceptive effects about 5.7 and 4.4 times more potent than those of morphine in the tail-flick (ED50=0.80 mg/kg) and hot-plate (ED50=0.93 mg/kg) tests, respectively. The antinociceptive effect of 7-hydroxymitragynine was significantly blocked by the mu1/mu2-opioid receptor antagonist beta-funaltrexamine hydrochloride (beta-FNA) and the mu1-opioid receptor-selective antagonist naloxonazine in both tests. Thus, 7-hydroxymitragynine acts predominantly on mu-opioid receptors, especially on mu1-opioid receptors. Isolated tissue studies further supported its specificity for the mu-opioid receptors. Further, 7-hydroxymintragynine dose-dependently (ED50=1.19 mg/kg, s.c.) and significantly inhibited gastrointestinal transit in mice, as morphine does. The inhibitory effect was significantly antagonized by beta-FNA pretreatment, but slightly antagonized by naloxonazine. The ED50 value of 7-hydroxymitragynine on gastrointestinal transit was larger than its antinociceptive ED50 value. On the other hand, morphine significantly inhibits gastrointestinal transit at a much smaller dose than its antinociceptive dose. These results suggest that mu-opioid receptor mechanisms mediate the antinociceptive effect and inhibition of gastrointestinal transit. This compound induced more potent antinociceptive effects and was less constipating than morphine.

Topics: Analgesics; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Gastrointestinal Transit; Guinea Pigs; Herbal Medicine; Ileum; Male; Mice; Mitragyna; Molecular Structure; Morphine; Muscle Contraction; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pain Measurement; Receptors, Opioid, mu; Secologanin Tryptamine Alkaloids; Thailand; Vas Deferens

The fact that galanin, beta-endorphin and their receptors are present in the arcuate nucleus of hypothalamus (ARC), coupled with our previous observation that both beta-endorphin and galanin play antinociceptive roles in pain modulation in the ARC, made it of interest to study their interactions. The hindpaw withdrawal latency (HWL) in response to noxious thermal and mechanical stimulation was assessed by the hot-plate test and the Randall Selitto Test. We showed that the antinociceptive effect induced by intra-ARC injection of galanin was dose-dependently attenuated by the following intra-ARC injection of naloxone. Furthermore, intra-ARC administration of the selective mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) attenuated the increased HWL induced by intra-ARC injection of galanin in a dose-dependent manner, while the delta-opioid receptor antagonist naltrindole or the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) did not. Moreover, intra-ARC injection of a galanin receptor antagonist galantide attenuated intraperitoneal morphine-induced increases in HWLs. These results demonstrate that the antinociceptive effect of galanin was related to the opioid system, especially mu-opioid receptor was involved in, and that systemic morphine induced antinociception involves galanin in the ARC.

Topics: Analgesics, Opioid; Animals; Arcuate Nucleus of Hypothalamus; Dose-Response Relationship, Drug; Galanin; Hindlimb; Male; Morphine; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Rats; Rats, Wistar; Receptors, Opioid

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

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

Women have a higher incidence of chronic pain syndromes than men and are generally more sensitive to experimental pain. Numerous studies have shown that the female gonadal hormones, estrogens, can profoundly affect the nervous and immune systems, including mechanisms involved in pain and nociception. In the present study, we used antagonists of estrogen receptors (ER) or mu-opioid receptors (mu OR) to evaluate the effects of estrogens on formalin-induced behavioural and immune responses in male rats. After two days of priming with 17 beta-estradiol or saline (i.c.v.), animals were subjected to the formalin test; 15 min prior to formalin (50 microl, 5%) or sham injection in the hind paw, animals were treated with an ER antagonist (ICI 182,780, ICI) or a mu OR antagonist (beta-funaltrexamine, FNA) or saline. The spontaneous behaviours, pain-related behaviours and interferon-gamma (IFN-gamma) production by peripheral blood mononuclear cells were studied in all groups. We found that central administration of estradiol increased the amount of licking of the formalin-injected paw in the second phase of the formalin test. Whereas ICI and FNA had no effect on pain behaviour in saline-pre-treated animals, both antagonists reversed the estradiol-induced increase in licking. The immune system was differently affected by formalin and estradiol treatment. Indeed, formalin injection per se decreased IFN-gamma production; estradiol had no effect on sham-injected animals but strongly reduce the decrease of IFN-gamma production in formalin-injected animals. The results demonstrate that centrally acting estrogens affect ER- and mu OR-mediated pain processing and influence immune function.

Topics: Animals; Behavior, Animal; Drug Interactions; Estradiol; Estrogen Antagonists; Fulvestrant; Injections, Intraventricular; Interferon-gamma; Male; Naltrexone; Narcotic Antagonists; Neuroimmunomodulation; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, mu

Antagonistic properties of buprenorphine for epsilon- and micro -opioid receptors were characterized in beta-endorphin- and [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-induced antinociception, respectively, with the tail-flick test in male ICR mice. epsilon-Opioid receptor agonist beta-endorphin (0.1-1 micro g), micro -opioid receptor agonist DAMGO (0.5-20 ng), or buprenorphine (0.1-20 micro g) administered i.c.v. dose dependently produced antinociception. The antinociception induced by 10 micro g of buprenorphine given i.c.v. was completely blocked by the pretreatment with beta-funaltrexamine (beta-FNA) (0.3 micro g i.c.v.), indicating that the buprenophine-induced antinociception is mediated by the stimulation of the micro -opioid receptor. The antinociceptive effects induced by beta-endorphin (1 micro g i.c.v.) and DAMGO (16 ng i.c.v.) were dose dependently blocked by pretreatment with smaller doses of buprenorphine (0.001-1 micro g i.c.v.), but not by a higher dose of buprenorphine (10 micro g i.c.v.). beta-FNA at a dose (0.3 micro g i.c.v.) that strongly attenuated DAMGO-induced antinociception had no effect on the antinociception produced by beta-endorphin (1 micro g i.c.v.). However, pretreatment with buprenorphine (0.1-10 micro g) in mice pretreated with this same dose of beta-FNA was effective in blocking beta-endorphin-induced antinociception. beta-FNA was 226-fold more effective at antagonizing the antinociception induced by DAMGO (16 ng i.c.v.) than by beta-endorphin (1 micro g i.c.v.). The antinociception induced by delta-opioid receptor agonist [d-Ala2]deltorphin II (10 micro g i.c.v.) or kappa1-opioid receptor agonist trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamine methanesulfonate salt [(-)-U50,488H] (75 micro g i.c.v.) was not affected by pretreatment with buprenorphine (0.1-1.0 micro g i.c.v.). It is concluded that buprenorphine, at small doses, blocks epsilon-opioid receptor-mediated beta-endorphin-induced antinociception and micro -opioid receptor-mediated DAMGO-induced antinociception, and at high doses produces a micro -opioid receptor-mediated antinociception.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; beta-Endorphin; Buprenorphine; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; 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

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

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

The effects of intracerebroventricular (icv) administration of endomorphin-2 (E2) on arterial blood pressure and pain threshold in spontaneously hypertensive rats (SHR) and modification of these effects by K [OP2] and mu [OP3] opioid receptors antagonists were investigated. Endomorphin-2 administrated icv in doses of 8, 16 and 32 mcg produced dose-dependent analgesic and hypotensive effect. In SHR decrease in blood pressure amounted 2.667, 4.0 and 6.534 kPa, respectively. Pain threshold increased by 1.7, 3.6 and 8.9 (g x 10). In Wistar Kyoto (WKY) strain, being the normotensive controls, E2 in doses of 8 and 16 mcg decrease in blood pressure was less pronounced and amounted 1.200 and 1.467 kPa, respectively, whereas the pain threshold increased by 7.2 and 10.4 (g x 10), respectively. Both E2 effects were antagonized by equimolar icv doses of beta-funaltrexamine (beta-FNA). Equimolar doses of nor-binaltorphimine (nor-BNI) attenuated analgesic action of E2, but were without hypotensive action produced by E2. A strong correlation between drop in blood pressure and increase in pain threshold observed in the SHR and WKY strains after icv administration of E2, indicate close interaction between systems responsible for pain perception and blood pressure control.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Blood Pressure; Disease Models, Animal; Drug Interactions; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Threshold; Rats; Rats, Inbred SHR; Rats, Inbred WKY

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

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

We investigated the role of mu-opioid receptor subtypes in both endomorphin-1 and endomorphin-2 induced antinociception in mice using supraspinally mediated behavior. With tail pressure as a mechanical noxious stimulus, both intracerebroventricularly (i.c.v.) and intrathecally (i.t.) injected-endomorphins produced potent and significant antinociceptive activity. Antinociception induced by i.t. and i.c.v. injection of endomorphin-1 was not reversed by pretreatment with a selective mu1-opioid receptor antagonist, naloxonazine (35 mg/kg, s.c.). By contrast, antinociception induced by i.t. and i.c.v. endomorphin-2 was significantly decreased by mu1-opioid receptor antagonist. Antinociception of both i.t. and i.c.v. endomorphin-1 and -2 was completely reversed by pretreatment with beta-funaltrexamine (40 mg/kg, s.c.). The results indicate that endomorphins may produce antinociception through the distinct mu1 and mu2 subtypes of mu-opioid receptor.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Injections, Intraventricular; Injections, Spinal; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Oligopeptides; Pain; Receptors, Opioid, mu; Time Factors

Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists.. Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, beta-funaltrexamine (beta-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through muu opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy.. The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression.. Naltrexone (0.01-1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. beta-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. beta-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene.. These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through mu opioid receptors. Overall, high doses of beta-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by beta-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects.

Topics: Animals; Dose-Response Relationship, Drug; Male; Naltrexone; Nociceptors; Pain; Rats

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 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

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 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

We examined whether mu-antisense (AS) oligodeoxynucleotide (oligo) treatment can be used in a manner similar to the mu-selective irreversible antagonist beta-funaltrexamine (beta-FNA) for in vivo pharmacology. Rats were injected intracerebroventricularly (icv) with a mu-AS or a missense (MS) oligo on days 1, 3, 5, 7, and 9 and were tested for the antinociceptive effect of sc injection of morphine on days 2, 4, 6, 8, and 10 in the cold water tail-flick (CWT) test. In another set of experiments, rats were also tested for the antinociceptive action of morphine twenty-four hours after icv injection of beta-FNA. Both beta-FNA and mu-AS produced rightward shifts in the dose-effect curves of morphine. In addition, pretreatment with 2.5 micrograms or more of beta-FNA or the mu-AS oligo for 5-9 days (but not for 1-3 days) reduced the maximal analgesic effect of morphine. The approximate fraction of functional receptor remaining for morphine was determined with the method of Furchgott to be 49.5% following 2.5 micrograms of beta-FNA; that after 5 days of the mu-AS oligo treatment was 50.8%. The results suggest that the mu-AS oligo can be used in the same manner as highly selective, irreversible mu opioid receptor ligands. Thus, properly designed AS oligos against receptors are of particular benefit when irreversible antagonists are not available. AS oligos represent a new class of selective and powerful pharmacological antagonists.

Topics: Animals; Base Sequence; Cerebral Ventricles; Injections, Intraventricular; Injections, Subcutaneous; Male; Molecular Sequence Data; Morphine; Naltrexone; Narcotic Antagonists; Oligonucleotides, Antisense; Pain; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, mu

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

We assessed the effect of naloxonazine, a selective mu 1-opioid receptor antagonist, on antinociception produced by intrathecal or intracerebroventricular injections of morphine in streptozotocin-induced diabetic mice. The antinociceptive effect of morphine (10 micrograms), administered i.c.v., was significantly less in diabetic mice than in non-diabetic mice. The antinociceptive effect of i.c.v. morphine was significantly reduced in both diabetic and non-diabetic mice following pretreatment with naloxonazine. There were no significant differences in the antinociceptive effect of morphine (1 microgram, i.t.) in diabetic and non-diabetic mice. Furthermore, naloxonazine had no significant effect on the antinociceptive effect of i.t. morphine in either diabetic or non-diabetic mice. On the other hand, the antinociceptive effects of i.c.v. and i.t. morphine were significantly reduced following pretreatment with beta-funaltrexamine, a selective mu-opioid receptor antagonist, in both diabetic and non-diabetic mice. In conclusion, mice with diabetes are selectively hyporesponsive to supraspinal mu 1-opioid receptor-mediated antinociception, but are normally responsive to activation of spinal mu 2-opioid receptors.

Topics: Analgesics; Animals; Diabetes Mellitus, Experimental; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; 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

SCH-32615 is a new enkephalinase inhibitor whose analgesic effects were examined following its stereotactic microinjection into the periaqueductal gray (PAG) and the ventromedial medulla (VMM) regions of the brainstem of the rat. SCH-32615 produced a strong, dose-dependent, naloxone-reversible analgesia to thermal noxious stimuli as measured by the hot plate test (HP; supraspinal analgesia) and the tail flick test (TF; spinal analgesia). The peak analgesic effect was seen within 10 min and remained for 45-60 min. ED50 were for PAG, HP = 10.7 micrograms and TF = 17.3 micrograms, and for VMM, HP = 5.7 micrograms and TF = 7.2 micrograms. Using the irreversible mu receptor antagonist, beta-funaltrexamine, it was found that the endogenous enkephalins in the PAG produce their analgesic effects by acting at only one receptor subtype (the mu receptor) while in the VMM both mu and delta opioid receptors are involved (not through the delta alone as previously believed).

Topics: Animals; Brain Stem; Dipeptides; Dose-Response Relationship, Drug; Medulla Oblongata; Microinjections; Naloxone; Naltrexone; Neprilysin; Pain; Periaqueductal Gray; Rats

The present studies were designed to determine whether streptozotocin-induced (STZ-induced) diabetes in mice can attenuate the development of antinociception induced by exposure to both foot shock and forced swimming stress. Foot shock stress produced significant analgesia both in control and diabetic mice. However, the extent of foot shock stress-induced analgesia (FSSIA) in diabetic mice was significantly lower than that in control mice. Naloxone (2 mg/kg, i.p.) significantly attenuated FSSIA in control mice, but was without effect on FSSIA in diabetic mice. One-minute swimming stress had no significant effect on tail-pinch latency in control mice, whereas 3-min swimming stress produced significant analgesia in these mice. Diabetic mice exhibited robust swimming stress-induced analgesia (SSIA): one-min swimming stress produced significant analgesia in diabetic mice. These analgesic effects were blocked by naltrindole, a selective antagonist of delta-opioid receptors, but not by pretreatment with beta-funaltrexamine, an irreversible and selective antagonist of mu-opioid receptors. These results suggest that the deficiency in the functioning of mu-opioid receptors caused by diabetes results in significant activation of an endogenous analgesic system, which is mediated mainly by delta-opioid receptors.

Topics: Animals; Diabetes Mellitus, Experimental; Male; Mice; Mice, Inbred ICR; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Physical Exertion; Receptors, Opioid, mu; Sensory Thresholds; Stress, Physiological

Morphine has been considered to be primarily a mu opiate receptor agonist. The present study was designed to determine if opiate receptor subtypes in addition to mu contribute to morphine analgesia at the level of the spinal cord. Extracellular activity of single wide dynamic range (WDR) neurons in the feline lumbar spinal cord were studied. Intrathecal administration of DAGO (selective mu agonist) or DPDPE (selective delta agonist) suppressed the noxiously (51 degrees C radiant heat) evoked activity of WDR neurons. Pretreatment with spinal beta-FNA (selective mu antagonist) antagonized the suppressive effects of spinal DAGO, but not that of DPDPE. Two doses of spinal morphine (200 and 400 micrograms) suppressed the noxiously evoked activity of WDR neurons confirming our previous report. Following beta-FNA pretreatment, the suppressive effects of morphine were reduced, however, when ICI 174,864 (selective delta antagonist) was co-administered with morphine on the spinal cord of the animals pretreated by beta-FNA, there was an even greater reduction in the neuronal suppression by morphine. Intravenous ICI 174,864 also reversed the suppressive effects of morphine in beta-FNA pretreated animals. beta-FNA antagonism of spinal morphine is evidence of the well-known mu receptor-mediating antinociception. However, antagonism by ICI 174,864 of morphine suppression in beta-FNA-pretreated animals demonstrates that morphine is capable of suppressing noxiously evoked activity of WDR neurons as a result of an interaction with delta receptors in addition to mu receptors at the level of spinal cord.

Topics: Analgesia; Animals; Cats; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Enkephalins; Evoked Potentials; Female; Hot Temperature; Injections, Spinal; Male; Morphine; Naltrexone; Narcotic Antagonists; Neurons; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord

Intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of morphine to mice antagonized the abdominal constriction induced by an i.p. injection of endothelin-1 (ET-1; 0.1 mg/kg). The ED50 values (95% confidence intervals) were 39.3 (16.5-80.2) ng and 1.5 (0.8-4.9) ng, respectively. The antagonism of ET-1-induced abdominal constriction by morphine was blocked by naloxone (1.0 mg/kg, s.c.) or by 24 h pretreatment with beta-funaltrexamine (beta-FNA; 8.84 micrograms, i.c.v.). These results demonstrate for the first time that the stimulus resulting from an i.p. injection of ET-1 is transmitted via ascending (pain) pathways that are subject to attenuation by opioid (mu) receptor activation. Hence, ET-1-induced abdominal constriction is a new pain model which, given the other pharmacology of ET-1, might represent a unique model with potential specific utility for anginal or other visceral pain.

Topics: Animals; Endothelins; Male; Mice; Morphine; Naloxone; Naltrexone; Pain; Pain Measurement

In a previous study, prolonged low-frequency muscle stimulation, inducing dynamic contractions in the hind leg of unanaesthetized rats, was shown to give rise to a hypoalgesia. The increase in pain threshold, measured as squeak threshold to noxious electric pulses, lasted 3 h. In the present study, the involvement of the endogenous opioid system in the post-stimulatory analgesia was investigated using selective opioid receptor antagonists. The post-stimulatory analgesia was completely reversed back to prestimulatory control levels by naloxone, 1 mg kg-1. ICI 154,129 and MR 2266 BS, selective delta- and kappa-receptor antagonists respectively, did not significantly influence the post-stimulatory analgesia, although ICI 154,129 had a minor pain threshold-lowering effect. Rats pretreated with beta-funaltrexamine, a mu-receptor antagonist, did not exhibit any post-stimulatory analgesia. These results suggest that opioid systems are involved in the increase in pain threshold after muscle stimulation and that the analgesic response is both elicited and maintained by the mu-receptor.

Topics: Analgesia; Animals; Electric Stimulation; Male; Muscles; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred SHR; Receptors, Opioid; Receptors, Opioid, mu

The formalin test assesses the behavioral response of an animal to minor tissue injury-induced pain. Opioid antinociception in this test has been suggested to depend largely on activation of kappa receptors but mu agonists are also potent in reducing pain behavior. The present study used the irreversible mu antagonist, beta-funaltrexamine (beta-FNA), to examine the role of mu receptor activation in this test. beta-FNA given intracranially 4 h before testing fully blocked the effects of morphine and attenuated the effects of ethylketocyclazocine and U50,488H. The results do not support a role for kappa receptors in antinociception in the formalin test. Instead, mu and, possibly, delta receptors are involved.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Dose-Response Relationship, Drug; Ethylketocyclazocine; Formaldehyde; Male; Morphine; Naltrexone; Narcotic Antagonists; Pain; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Urination

Determinations were made of the effects of beta-funaltrexamine (beta-FNA), an irreversible mu-opioid receptor antagonist, on the day-night rhythm of nociception in male mice. Peripheral administration of beta-FNA (20 and 40 mg/kg) disrupted the day-night rhythm of foot-licking response to aversive thermal (50 degrees C) stimulation. The peak nocturnal response latency was attenuated and the marked increases and decreases in response latency present at the light-dark and dark-light transitions, respectively, were suppressed. These results suggest that mu opioids are associated with the generation and expression of the day-night rhythm of this particular measure of nociception in mice.

Topics: Animals; Circadian Rhythm; Male; Mice; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid; Receptors, Opioid, mu

Morphine administered concurrently by i.c.v. plus intrathecal (i.t.) injection produces a multiplicative (synergistic) interaction for antinociception in the tail-flick test. Inasmuch as i.c.v. administered beta-endorphin has been proposed to produce antinociception by activating a descending pain inhibitory system different from that activated by morphine, the present experiments compared the two systems in mice. The responses to i.c.v., i.t. and combinations of i.c.v. plus i.t. administration of morphine and beta-endorphin were evaluated by determination of ED50 values which were plotted as isobolograms and compared to calculated theoretical additive ED50 values. The following combinations gave additive interactions: i.c.v. plus i.t. beta-endorphin, i.c.v. beta-endorphin plus i.t. morphine and i.t. morphine plus i.t. beta-endorphin. These results were consistent with the hypothesis that i.c.v. beta-endorphin stimulates supraspinal epsilon receptors which activate a descending pathway involving enkephalinergic neuronal mediation and spinal postsynaptic mu receptors. Stimulation of these mu receptors by i.t. morphine or i.t. beta-endorphin together with the supraspinal effect of beta-endorphin resulted in an additive interaction. Multiplicative interactions were obtained for the following combinations: i.c.v. morphine plus i.t. morphine, i.c.v. morphine plus i.t. beta-endorphin and i.c.v. morphine plus i.c.v. beta-endorphin. Morphine administered i.c.v. stimulated supraspinal mu receptors to activate a descending pain inhibitory pathway which is mediated spinally by monoamines. The i.t. agonists in this case activated the spinal mu receptor which is presumed to be part of the beta-endorphin descending pathway described above. Thus, when both pathways were activated simultaneously the interaction was multiplicative.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesia; Animals; beta-Endorphin; Drug Tolerance; Efferent Pathways; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Naltrexone; Pain; Spinal Cord

The present study compared the effects of two opioid antagonists, beta-funaltrexamine (beta-FNA) and 16-methyl cyprenorphine (RX8008M) on the antinociception produced by a range of opioid agonists in the abdominal constriction test in the mouse and the paw pressure test in the guinea-pig. Both antagonists produced large shifts in the dose-response curves to the mu-agonists, morphine and fentanyl, confirming their mu-antagonist activity. Neither antagonist produced any antagonism of the antinociceptive effects of the selective kappa-agonists U50488, U69593 and tifluadom, in the mouse. However, RX8008M produced small shifts in the dose-response curves to these agonists in the guinea-pig, which seems more likely to reflect mu-receptor activity of the agonists in the guinea-pig than lack of selectivity of the antagonists. Both beta-FNA and RX8008M produced some antagonism of bremazocine, ethyl-ketocyclazocine, proxorphan and butorphanol, indicating that these agonists have a prominent mu-receptor component to their antinociceptive actions.

Topics: Abdomen; Animals; Guinea Pigs; Male; Mice; Morphinans; Muscle Contraction; Naltrexone; Narcotic Antagonists; Narcotics; Nociceptors; Pain

The possibility that the opioid delta-receptor mediates antinociception in tests where heat is the noxious stimulus was investigated using highly selective mu- and delta-agonist and -antagonists. Antinociceptive dose-response curves were constructed for mu ([D-Ala2,NMePhe4,Gly-ol]enkephalin, DAGO; morphine) and delta ([D-Pen2,D-Pen5]enkephalin, DPDPE)-agonists in the absence, and in the presence of the mu non-surmountable antagonist, beta-funaltrexamine (beta-FNA) or the delta-antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, where Aib is alpha-amino-isobutyric acid). Agonists and ICI 174,864 were given alone in the same intracerebroventricular (i.c.v.) or intrathecal (i.th.) injection to mice 20 min prior to testing in the warm-water (55 degrees C) tail-withdrawal test (+10 min for i.th. DPDPE); beta-FNA was given as a single i.c.v. or i.th. pretreatment dose (20 and 0.01 nM, respectively) 4 h prior to testing. I.c.v. pretreatment with beta-FNA resulted in a rightward displacement of the DAGO and morphine antinociceptive dose-response lines, but failed to displace the i.c.v. DPDPE curve. Similarly, i.th. pretreatment with beta-FNA displaced the i.th. morphine dose-response curve to the right without affecting the i.th. DPDPE antinociceptive dose-response line. ICI 174,864 (1 and 3 micrograms) produced a dose-related antagonism of i.c.v. or i.th. DPDPE, but did not alter the antinociceptive effects of DAGO or morphine given by the same routes. Co-administration of ICI 174,864 (3 micrograms) with i.c.v. morphine in beta-FNA pretreated (but not control) mice resulted in a further rightward displacement of the morphine dose-response line.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Dose-Response Relationship, Drug; Drug Combinations; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Enkephalins; Hot Temperature; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Naltrexone; Nociceptors; Pain; Receptors, Opioid; Receptors, Opioid, delta; Spinal Cord

Exposure to either cold or warm stress increased the thermal nociceptive thresholds of the terrestrial snail, Cepaea nemoralis. The warm stress-induced 'analgesia' was blocked by the prototypic opiate antagonist, naloxone, and the delta-opiate antagonist, ICI 154,129, and was suppressed by a 24-h pretreatment with the irreversible opiate antagonist, beta-funaltrexamine (B-FNA). In contrast, cold stress-induced analgesia was unaffected by either naloxone, ICI 154,129 or B-FNA. These results indicate that this mollusc displays both opioid and non-opioid forms of stress-induced analgesia in a manner analogous to that reported for mammals. These findings suggest an early evolutionary development and phylogenetic continuity of opioid and non-opioid mediated stress responses to aversive environmental stimuli.

Topics: Animals; Cold Temperature; Endorphins; Enkephalin, Leucine; Hot Temperature; Naloxone; Naltrexone; Pain; Reaction Time; Snails; Stress, Physiological

The icv injection of morphine or DADLE ED50 a few min before the alkylating agent beta-FNA resulted in complete protection of their respective analgesic effects when evaluated 24h later, although a little cross-protection could be observed. The analgesia evoked by DADLE was partially protected using higher doses of morphine before beta-FNA. However, higher doses of DADLE did not protect the analgesia induced by morphine. On the other hand, the antagonistic action of KCl on opioid analgesia was found to be dependent on the opioid utilized to protect the opioid receptor against the effect of beta-FNA. These results are discussed in terms of multiple receptors mediating opioid analgesia at supraspinal level in the mouse.

Topics: Analgesia; Animals; Enkephalins; Male; Mice; Mice, Inbred Strains; Morphine; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid

The effect of the irreversible opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on antinociception produced by mu- and kappa-receptor agonists was studied in the rat. beta-FNA, 20 to 80 mg kg-1, s.c., given 24 h before testing, produced a dose-related antagonism of the effects of morphine in the paw pressure, hotplate and tail-flick tests. Following the 80 mg kg-1 dose, the degree of antagonism of morphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days. In the paw pressure test, beta-FNA, 40 mg kg-1, s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective kappa-agonist, U-50,488. In light of these results, the possible opioid receptor selectivities of both the agonists and beta-FNA are reassessed.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Buprenorphine; Cyclazocine; Ethylketocyclazocine; Fentanyl; Male; Naltrexone; Pain; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The antinociceptive properties of morphine (mu), ethylketazocine (kappa), nalorphine (kappa), [D-Ala2, D-Leu5]enkephalin (delta) and [D-Ala2, Met5]enkephalinamide (mu, delta) were assessed using the radiant heat tail-flick and acetic acid-induced writhing assays in mice. The apparent pA2 values for the interaction of naloxone with morphine were the same regardless of the nociceptive stimulus employed or the route of administration of morphine. The apparent pA2 values for the interactions of naloxone with ethylketazocine and nalorphine in the writhing test differed significantly from that for the interaction of morphine and naloxone. Nalorphine did not produce a consistent antinociceptive effect on the tail-flick test. The apparent pA2 values for the interaction of ethylketazocine (s.c. or i.c.v.) with naloxone were similar to those for morphine-naloxone interactions on the tail-flick assay. The apparent pA2 values for the interactions of naloxone with [D-Ala2, D-Leu5] enkephalin differed from those for morphine-naloxone interactions on the writhing test. The highly selective mu antagonist beta-funaltrexamine antagonized the agonist actions of morphine and [D-Ala2, D-Leu5]enkephalin, and, in a previous study, beta-funaltrexamine antagonized the antinociceptive actions of [D-Ala2, Met5]enkephalinamide, but not those of nalorphine. It was concluded that agonist interaction with mu or kappa receptors can result in antinociceptive effects in the acetic acid-induced writhing test, and that an agonist interaction with mu, but not kappa, receptors results in antinociceptive action on the radiant heat tail-flick test, and furthermore, that a possible combination of mu and delta receptor interaction can result in antinociceptive activity in both tests.

Topics: Acetates; Acetic Acid; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Female; Hot Temperature; Male; Mice; Naloxone; Naltrexone; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

The long-acting opiate antagonistic potency of naloxazone (NXZ), beta-chlornaltrexamine (beta-CNA) and beta-funaltrexamine (beta-FNA) was compared using three inbred strains of mice, in which morphine induces either analgesia (DBA/2), locomotion (C57BL/6), or both responses (C3H/He). The antagonists were applied SC 24-120 hr before morphine (10 or 20 mg/kg, IP), followed by the tests after 30 min. The minimal dose which completely antagonized morphine-induced analgesia in DBA and locomotion in C57 mice during 24 hr were: for NXZ 50 and 100 mg/kg, for beta-CNA 0.8 and 6.2 mg/kg, for beta-FNA 1.6 and 12.5 mg/kg, respectively. beta-FNA and beta-CNA more potently blocked morphine-induced analgesia in DBA mice than the activity response in the C57 strain. In contrast, beta-FNA prevented morphine-induced locomotion at a lower dose (6.2 mg/kg) than analgesia (greater than 50 mg/kg) in C3H mice, while beta-CNA was equipotent (1.6 mg/kg). In general, beta-CNA turned out to be the most reactive compound, antagonizing morphine effects in low doses up to 120 hr. beta-FNA selectively antagonized either morphine-induced analgesia or locomotion, depending on the strain used. This suggests that a given morphine response might be caused by a genetically determined multiplicity of opiate receptor types and their mutual interactions.

Topics: Animals; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Morphine; Motor Activity; Naloxone; Naltrexone; Pain; Species Specificity

The profile of action of beta-funaltrexamine (beta-FNA), the fumaramate methyl ester derivative of naltrexone, on antinociceptive tests in vivo was investigated. Beta-FNA demonstrated antinociceptive actions that were of short duration and that appeared to be mediated by kappa receptor interaction. In contrast, the antagonist actions of beta-FNA were of remarkably long duration and were selective toward nu agonist interactions. This profile of action is consistent with the profile of action of beta-FNA in vitro. The selective long-lasting antagonism of mu-mediated effects by beta-FNA may be of great value in the elucidation of multiple opioid receptor function.

Topics: Acetates; Acetic Acid; Analgesics, Opioid; Animals; Drug Interactions; Female; Male; Mice; Morphine; Nalorphine; Naloxone; Naltrexone; Narcotics; Pain; Reaction Time