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1.
Peptides ; 161: 170943, 2023 03.
Article in English | MEDLINE | ID: mdl-36621672

ABSTRACT

The most commonly used opioid analgesics are limited by their severe side-effects in the clinical treatment of pain. Preliminary reports indicate that the combination of classical opioids and N/OFQ receptor (NOP) ligands may be an effective strategy to reduce unwanted side-effects and improve antinociception. But the interaction of these two receptor ligands in pain regulation at the peripheral level remains unclear. In this study, the antinociception of a designed amide analogue of the mu opioid receptor (MOP) peptide agonist DAMGO, DAMGO-NH2, and its antinociceptive interaction with the peripherally limited NOP peptide agonist NOP01 was investigated in two mouse models of formalin pain. Our results showed that DAMGO-NH2 acted as a MOP agonist in in vitro functional assays. Moreover, local subcutaneous or intraplantar injection of DAMGO-NH2 exerted dose-related antinociception in both phases of the formalin orofacial and intraplantar pain, which could be mediated by the classical opioid receptor. Peripheral but not central pretreatment with the peripherally restricted opioid antagonist naloxone methiodide inhibited local DAMGO-NH2-induced antinociception, supporting the involvement of the peripheral opioid receptor in local DAMGO-NH2-induced antinociception. Furthermore, co-administration of the inactive doses of DAMGO-NH2 and NOP01 produced effective antinociception. More importantly, isobolographic analysis indicates that the combination of DAMGO-NH2 and NOP01 elicited supra-additive antinociception in these two models of formalin pain. In addition, the combination of DAMGO-NH2 and NOP01 did not change motor function of mice in rotarod test. In conclusion, these data suggest that peripheral DAMGO-NH2 and particularly its combination therapy with NOP01 may be effective for pain management.


Subject(s)
Analgesics, Opioid , Pain , Receptors, Opioid , Animals , Mice , Analgesics/pharmacology , Analgesics/therapeutic use , Analgesics, Opioid/pharmacology , Analgesics, Opioid/therapeutic use , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Ligands , Nociceptin Receptor , Pain/drug therapy , Peptides/therapeutic use , Receptors, Opioid/agonists , Receptors, Opioid, mu/agonists , Drug Interactions
2.
J Neurosci ; 42(16): 3316-3328, 2022 04 20.
Article in English | MEDLINE | ID: mdl-35256532

ABSTRACT

Opioid tolerance (OT) leads to dose escalation and serious side effects, including opioid-induced hyperalgesia (OIH). We sought to better understand the mechanisms underlying this event in the gastrointestinal tract. Chronic in vivo administration of morphine by intraperitoneal injection in male C57BL/6 mice evoked tolerance and evidence of OIH in an assay of colonic afferent nerve mechanosensitivity; this was inhibited by the δ-opioid receptor (DOPr) antagonist naltrindole when intraperitoneally injected in previous morphine administration. Patch-clamp studies of DRG neurons following overnight incubation with high concentrations of morphine, the µ-opioid receptors (MOPr) agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin (DAMGO) or the DOPr agonist [D-Ala2, D-Leu5]-Enkephalin evoked hyperexcitability. The pronociceptive actions of these opioids were blocked by the DOPr antagonist SDM25N but not the MOPr antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 The hyperexcitability induced by DAMGO was reversed after a 1 h washout, but reapplication of low concentrations of DAMGO or [D-Ala2, D-Leu5]-Enkephalin restored the hyperexcitability, an effect mediated by protein kinase C. DOPr-dependent DRG neuron hyperexcitability was blocked by the endocytosis inhibitor Pitstop 2, and the weakly internalizing DOPr agonist ARM390 did not cause hyperexcitability. Bioluminescence resonance energy transfer studies in HEK cells showed no evidence of switching of G-protein signaling from Gi to a Gs pathway in response to either high concentrations or overnight incubation of opioids. Thus, chronic high-dose opioid exposure leads to opioid tolerance and features of OIH in the colon. This action is mediated by DOPr signaling and is dependent on receptor endocytosis and downstream protein kinase C signaling.SIGNIFICANCE STATEMENT Opioids are effective in the treatment of abdominal pain, but escalating doses can lead to opioid tolerance and potentially opioid-induced hyperalgesia. We found that δ-opioid receptor (DOPr) plays a central role in the development of opioid tolerance and opioid-induced hyperalgesia in colonic afferent nociceptors following prolonged exposure to high concentrations of MOPr or DOPr agonists. Furthermore, the role of DOPr was dependent on OPr internalization and activation of a protein kinase C signaling pathway. Thus, targeting DOPr or key components of the downstream signaling pathway could mitigate adverse side effects by opioids.


Subject(s)
Analgesics, Opioid , Morphine , Analgesics, Opioid/adverse effects , Animals , Drug Tolerance , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Gastrointestinal Tract , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Male , Mice , Mice, Inbred C57BL , Morphine/pharmacology , Morphine/therapeutic use , Narcotic Antagonists/pharmacology , Protein Kinase C , Receptors, Opioid , Receptors, Opioid, mu , Signal Transduction
3.
J Neurosci ; 40(35): 6812-6819, 2020 08 26.
Article in English | MEDLINE | ID: mdl-32690616

ABSTRACT

Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine precursor L-DOPA, but its prolonged usage causes dyskinesias referred to as L-DOPA-induced dyskinesia (LID). Several studies in animal models of PD have suggested that dyskinesias are associated with a heightened opioid cotransmitter tone, observations that have led to the notion of a LID-related hyperactive opioid transmission that should be corrected by µ opioid receptor antagonists. Reports that both antagonists and agonists of the µ opioid receptor may alleviate LID severity in primate models of PD and LID, together with the failure of nonspecific antagonist to improve LID in pilot clinical trials in patients, raises doubt about the reliability of the available data on the opioid system in PD and LID. After in vitro characterization of the functional activity at the µ opioid receptor, we selected prototypical agonists, antagonists, and partial agonists at the µ opioid receptor. We then showed that both oral and discrete intracerebral administration of a µ receptor agonist, but not of an antagonist as long thought, ameliorated LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned female macaque model of PD and LID. The results call for a reappraisal of opioid pharmacology in the basal ganglia as well as for the development of brain nucleus-targeted µ opioid receptor agonists.SIGNIFICANCE STATEMENT µ opioid receptors have long been considered as a viable target for alleviating the severity of L-DOPA-induced hyperkinetic side effects, induced by the chronic treatment of Parkinson's disease motor symptoms with L-DOPA. Conflicting results between experimental parkinsonism and Parkinson's disease patients, however, dampened the enthusiasm for the target. Here we reappraise the pharmacology and then demonstrate that both oral and discrete intracerebral administration of a µ receptor agonist, but not of an antagonist as long thought, ameliorates LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease, calling for a reappraisal of the opioid pharmacology as well as for the development of brain nucleus-targeted µ receptor agonists.


Subject(s)
Dyskinesias/drug therapy , MPTP Poisoning/physiopathology , Receptors, Opioid, mu/agonists , Animals , CHO Cells , Cricetinae , Cricetulus , Dyskinesias/etiology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/administration & dosage , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Female , Humans , Levodopa/adverse effects , Levodopa/therapeutic use , MPTP Poisoning/drug therapy , Macaca fascicularis , Neurotransmitter Agents/administration & dosage , Neurotransmitter Agents/pharmacology , Neurotransmitter Agents/therapeutic use , Receptors, Opioid, mu/antagonists & inhibitors
4.
Physiol Res ; 68(3): 375-384, 2019 06 30.
Article in English | MEDLINE | ID: mdl-30904005

ABSTRACT

The objectives of this study were to investigate the role of endogenous opioids in the mediation of stress-induced cardiomyopathy (SIC), and to evaluate which opioid receptors regulate heart resistance to immobilization stress. Wistar rats were subjected to 24 h immobilization stress. Stress-induced heart injury was assessed by 99mTc-pyrophosphate accumulation in the heart. The opioid receptor (OR) antagonists (naltrexone, NxMB - naltrexone methyl bromide, MR 2266, ICI 174.864) and agonists (DALDA, DAMGO, DSLET, U-50,488) were administered intraperitoneally prior to immobilization and 12 h after the start of stress. In addition, the selective micro OR agonists PL017 and DAMGO were administered intracerebroventricularly prior to stress. Finally pretreatment with guanethidine was used. Naltrexone did not alter the cardiac 99mTc-PP accumulation in stressed rats. NxMB aggravated stress-induced cardiomyopathy (P=0.005) (SIC). The selective micro OR agonist DALDA, which does not cross the blood-brain barrier, completely prevented (P=0.006) SIC. The micro OR agonist DAMGO exhibited weaker effect than DALDA. The selective delta ligand (DSLET) and kappa OR ligand (U-50,488) did not alter stress-induced 99mTc-pyrophosphate accumulation in the heart. Intracerebroventricular administration of the micro OR agonists aggravated SIC. Pretreatment with guanethidine abolished this effect (P=0.01). Guanethidine alone exhibited cardioprotective properties. A stimulation of central micro OR promotes an appearance of SIC. In contrast, stimulation of peripheral micro OR contributes to an increase in cardiac tolerance to stress.


Subject(s)
Analgesics, Opioid/therapeutic use , Cardiotonic Agents/therapeutic use , Heart Diseases/metabolism , Heart Diseases/prevention & control , Myocardium/metabolism , Stress, Psychological/metabolism , Analgesics, Opioid/pharmacology , Animals , Cardiotonic Agents/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Heart Diseases/chemically induced , Immobilization/adverse effects , Immobilization/psychology , Male , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Rats , Rats, Wistar , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/metabolism , Stress, Psychological/psychology
5.
Bull Exp Biol Med ; 163(2): 177-179, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28726190

ABSTRACT

We studied the rate of development of tolerance to the ethanol-induced analgesia under the effect of µ-, δ-, and κ-opioid agonists and antagonists not crossing the blood-brain barrier and rapidly inactivated by gastric and duodenal proteolytic enzymes. Activation of gastric κ-opioid receptors eliminated the analgesic effect of ethanol and accelerated the development of tolerance to ethanol-induced analgesia. In contrast, activation of gastric µ-opioid receptors decelerated the development of this tolerance. Activation of gastric δ-opioid receptors produced no effect on examined tolerance. µ-Opioid receptor antagonist decelerated and δ-opioid receptor antagonist accelerated the development of tolerance to ethanol-induced analgesia. Thus, the state of gastric opioid receptors affects the manifestation of ethanol-induced analgesia and the development of tolerance to this effect.


Subject(s)
Ethanol/therapeutic use , Receptors, Opioid/metabolism , Analgesia/methods , Analgesics, Opioid/therapeutic use , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Enkephalin, Leucine-2-Alanine/therapeutic use , Estradiol/analogs & derivatives , Estradiol/therapeutic use , Fulvestrant , Male , Narcotic Antagonists/therapeutic use , Pain Management , Pain Measurement , Quetiapine Fumarate/therapeutic use , Rats , Rats, Wistar , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Somatostatin/analogs & derivatives , Somatostatin/therapeutic use
6.
Brain Res Bull ; 125: 211-7, 2016 07.
Article in English | MEDLINE | ID: mdl-27450703

ABSTRACT

Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia. In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness. Behavioral pharmacology experiments were performed to compare the effects of DAMGO, a selective agonist for µ-opioid receptor (MOR), ACPA, a specific agonist for CB1, and combinations of DAMGO and ACPA in attenuating complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia in the rat hindpaw. DAMGO (1µg-1mg) or ACPA (1µg-2mg) was administered into the inflamed paw when mechanical hyperalgesia was fully developed. When administered individually, DAMGO and ACPA dose-dependently reversed the mechanical hyperalgesia. DAMGO displayed a lower ED50 value (57.4±2.49µg) than ACPA (111.6±2.18µg), but ACPA produced longer lasting antihyperalgesic effects. Combinations of DAMGO and ACPA also dose-dependently attenuated mechanical hyperalgesia, but the antihyperalgesic effects were partial and transient even at high doses. Using isobolographic analysis, we determined that combined treatment with DAMGO and ACPA produced antagonistic effects with the observed ED50 of 128.4±2.28µg. Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate mechanical hyperalgesia when administered individually, but exert opposing effects when administered together. The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined drug treatments in chronic pain conditions can be optimized.


Subject(s)
Analgesics, Opioid/therapeutic use , Cannabinoid Receptor Agonists/therapeutic use , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Inflammation/complications , Analysis of Variance , Animals , Arachidonic Acids/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Freund's Adjuvant/toxicity , Inflammation/chemically induced , Male , Rats , Rats, Sprague-Dawley
7.
Spinal Cord ; 54(10): 767-777, 2016 Oct.
Article in English | MEDLINE | ID: mdl-26927293

ABSTRACT

OBJECTIVE: The current study aimed to evaluate the contribution(s) of specific opioid receptor systems to the analgesic and detrimental effects of morphine, observed after spinal cord injury in prior studies. STUDY DESIGN: We used specific opioid receptor agonists to assess the effects of µ- (DAMGO), δ- (DPDPE) and κ- (GR89696) opioid receptor activation on locomotor (Basso, Beattie and Bresnahan scale, tapered beam and ladder tests) and sensory (girdle, tactile and tail-flick tests) recovery in a rodent contusion model (T12). We also tested the contribution of non-classic opioid binding using [+]- morphine. METHODS: First, a dose-response curve for analgesic efficacy was generated for each opioid agonist. Baseline locomotor and sensory reactivity was assessed 24 h after injury. Subjects were then treated with an intrathecal dose of a specific agonist and re-tested after 30 min. To evaluate the effects on recovery, subjects were treated with a single dose of an agonist and both locomotor and sensory function were monitored for 21 days. RESULTS: All agonists for the classic opioid receptors, but not the [+]- morphine enantiomer, produced antinociception at a concentration equivalent to a dose of morphine previously shown to produce strong analgesic effects (0.32 µmol). DAMGO and [+]- morphine did not affect long-term recovery. GR89696, however, significantly undermined the recovery of locomotor function at all doses tested. CONCLUSIONS: On the basis of these data, we hypothesize that the analgesic efficacy of morphine is primarily mediated by binding to the classic µ-opioid receptor. Conversely, the adverse effects of morphine may be linked to activation of the κ-opioid receptor. Ultimately, elucidating the molecular mechanisms underlying the effects of morphine is imperative to develop safe and effective pharmacological interventions in a clinical setting. SETTING: USA. SPONSORSHIP: Grant DA31197 to MA Hook and the NIDA Drug Supply Program.


Subject(s)
Analgesics, Opioid/therapeutic use , Recovery of Function/drug effects , Spinal Cord Injuries/drug therapy , Analysis of Variance , Animals , Body Weight/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Enkephalin, D-Penicillamine (2,5)-/therapeutic use , Locomotion/drug effects , Male , Morphine/therapeutic use , Pain Measurement , Piperazines/therapeutic use , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley , Severity of Illness Index , Spinal Cord Injuries/physiopathology
8.
Bull Exp Biol Med ; 159(6): 722-5, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26519265

ABSTRACT

We studied the effects of µ-opioid receptor activation in vivo and in vitro on the tolerance of isolated perfused rat heart to global ischemia (45 min) and reperfusion (30 min). Stimulation of µ-receptors in vivo by intraperitoneal administration of µ-opioid receptor agonist DAMGO (0.1 mg/kg) reduced reperfusion release of creatinine phosphokinase and promoted aggravation of postischemic systolic and diastolic dysfunction of the isolated heart. Activation of µ-opioid receptors in vitro by addition of selective agonist DAMGO in a concentration of 170 nM to perfusion solution had no effect on necrotic death of cardiomyocytes and aggravated reperfusion stunning of the heart.


Subject(s)
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Myocardial Contraction/drug effects , Myocardial Ischemia , Myocardial Reperfusion Injury , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Animals , Cell Death/drug effects , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Heart/drug effects , Heart/physiology , Male , Myocardial Ischemia/pathology , Myocardial Ischemia/physiopathology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardium/pathology , Necrosis , Organ Culture Techniques , Rats , Rats, Wistar , Receptors, Opioid, mu/agonists , Reperfusion
9.
PLoS One ; 10(3): e0122924, 2015.
Article in English | MEDLINE | ID: mdl-25807259

ABSTRACT

Unilateral ligation of the tendon of anterior superficial part of rat masseter muscle (TASM) leads to long-lasting allodynia. Sex differences in peripheral mu-opioid receptor (MOR)-mediated analgesia under persistent myogenic pain are not well understood. In this study, we examined (1) whether locally applied MOR agonists attenuate persistent pain following TASM ligation in a sex dependent manner, (2) whether there are sex differences of MOR expression changes in rat trigeminal ganglia (TG). The effects of MOR agonist, D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt (DAMGO), were assessed 14 days after TASM ligation in male, female and orchidectomized (GDX) male rats. MOR mRNA and protein levels in TG 14 days following tendon ligation were also determined. The mechanical thresholds of the injured side were significantly decreased in both male and female rats, from 3 days to 28 days after TASM ligation. A10 µg DAMGO significantly attenuated allodynia in male rats. A 10-fold higher dose of DAMGO was required in female and GDX male rats to produce the level of anti- allodynia achieved in male rats. The level of MOR mRNA in TG from male rats was significantly greater 14 days after TASM ligation compared with the sham-operated male rats, but not from female and GDX male rats. After TASM ligation, males had significantly more MOR immunoreactivity in TG compared to sham-operated males. The MOR levels increased to 181.8% of the sham level in male rats receiving tendon injury. But there was no significant change in female rats receiving tendon injury compared to the sham female rats. Taken together, our data suggest that there were sex differences in the effects of peripheral MOR agonists between male and female rats under TASM ligation developing long-lasting pain condition, which is partly mediated by sex differences in the changes of MOR expressions and testosterone is an important factor in the regulation of MOR.


Subject(s)
Analgesics, Opioid/therapeutic use , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Facial Pain/drug therapy , Receptors, Opioid, mu/metabolism , Analgesics, Opioid/pharmacology , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Facial Pain/etiology , Facial Pain/veterinary , Female , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Hyperalgesia/pathology , Immunohistochemistry , Male , Orchiectomy , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/genetics , Sex Characteristics , Tendon Injuries/complications , Tendon Injuries/pathology , Trigeminal Ganglion/metabolism , Trigeminal Ganglion/pathology
10.
PLoS One ; 9(8): e104420, 2014.
Article in English | MEDLINE | ID: mdl-25105291

ABSTRACT

The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10-20 µg), DAMGO (1-2 µg) and U50,488H (25-50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg), deltorphin II (1.5-15 µg) and SNC80 (10-20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.


Subject(s)
Analgesics, Opioid/therapeutic use , Microglia/drug effects , Neuralgia/drug therapy , Receptors, Opioid, delta/agonists , Receptors, Opioid, delta/metabolism , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/administration & dosage , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/therapeutic use , Analgesics, Opioid/administration & dosage , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Cells, Cultured , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/administration & dosage , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Gene Expression Regulation/drug effects , Male , Microglia/cytology , Microglia/metabolism , Minocycline/administration & dosage , Minocycline/therapeutic use , Morphine/administration & dosage , Morphine/therapeutic use , Rats, Wistar , Receptors, Opioid, delta/genetics
11.
Bull Exp Biol Med ; 156(6): 778-80, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24824695

ABSTRACT

We studied the effect of peripheral µ- and κ-opioid receptor agonists (not crossing the bloodbrain barrier) on locomotor activity and metabolism in rats after acute administration of ethanol. Intraperitoneal injection of ethanol in a single dose of 2 g/kg had a strong depressive effect manifested in a decrease in horizontal locomotor activity and suppression of metabolism. µ-Opioid receptor agonist DAMGO and κ-opioid receptor agonist ICI 204,448 partly abolished the effect of ethanol on locomotor activity of rats. ICI 204,448 was most potent in this respect. In contrast to µ-opioid receptor agonist DAMGO, κ-opioid receptor agonist ICI 204,448 prevented metabolism suppression induced by ethanol. Our results indicate that ICI 204,448 significantly inhibits the depressive effect of ethanol. DAMGO showed only partial effectiveness under these experimental conditions.


Subject(s)
Central Nervous System Depressants/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Ethanol/pharmacology , Receptors, Opioid, kappa/agonists , Receptors, Opioid, mu/agonists , Analgesics, Opioid/therapeutic use , Animals , Blood-Brain Barrier/metabolism , Energy Metabolism/drug effects , Male , Motor Activity/drug effects , Pyrrolidines/therapeutic use , Rats , Rats, Wistar
12.
Neuroscience ; 267: 67-82, 2014 May 16.
Article in English | MEDLINE | ID: mdl-24583035

ABSTRACT

Opiate analgesia in the spinal cord is impaired during neuropathic pain. We hypothesized that this is caused by a decrease in µ-opioid receptor inhibition of neurotransmitter release from primary afferents. To investigate this possibility, we measured substance P release in the spinal dorsal horn as neurokinin 1 receptor (NK1R) internalization in rats with chronic constriction injury (CCI) of the sciatic nerve. Noxious stimulation of the paw with CCI produced inconsistent NK1R internalization, suggesting that transmission of nociceptive signals by the injured nerve was variably impaired after CCI. This idea was supported by the fact that CCI produced only small changes in the ability of exogenous substance P to induce NK1R internalization or in the release of substance P evoked centrally from site of nerve injury. In subsequent experiments, NK1R internalization was induced in spinal cord slices by stimulating the dorsal root ipsilateral to CCI. We observed a complete loss of the inhibition of substance P release by the µ-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) in CCI rats but not in sham-operated rats. In contrast, DAMGO still inhibited substance P release after inflammation of the hind paw with complete Freund's adjuvant and in naïve rats. This loss of inhibition was not due to µ-opioid receptor downregulation in primary afferents, because their colocalization with substance P was unchanged, both in dorsal root ganglion neurons and primary afferent fibers in the dorsal horn. In conclusion, nerve injury eliminates the inhibition of substance P release by µ-opioid receptors, probably by hindering their signaling mechanisms.


Subject(s)
Pain/drug therapy , Receptors, Opioid, mu/metabolism , Sciatica/drug therapy , Sciatica/metabolism , Substance P/metabolism , Analgesics, Opioid/therapeutic use , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Ganglia, Spinal/cytology , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Inflammation/chemically induced , Inflammation/complications , Inflammation/etiology , Male , Neurons/drug effects , Neurons/metabolism , Pain/etiology , Pain/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Neurokinin-1/metabolism , Sciatic Nerve/drug effects , Spinal Cord/drug effects , Spinal Cord/pathology
13.
Brain Res Bull ; 87(2-3): 238-43, 2012 Feb 10.
Article in English | MEDLINE | ID: mdl-22079588

ABSTRACT

This study describes the antinociceptive effects of µ-opioid agonists, d-Ala(2),N-Me-Phe(4),Gly(5)-ol-enkephalin (DAMGO) and morphine in a model of rat visceral pain in which nociceptive responses were triggered by 2% acetic acid intraperitoneal (i.p.) injections. DAMGO and morphine were administered i.p., to the same site where acetic acid was delivered or intracerebroventricularly (i.c.v.). The antinociceptive actions of i.p. versus i.c.v. administered DAMGO or morphine were evaluated in the late phase of permanent visceral nociceptive responses. Both compounds inhibited the nociceptive responses in a dose-dependent manner and exhibited more potent agonist activity after i.c.v. than i.p. administration. DAMGO and morphine showed comparable ED(50) values after i.p. injections. However, DAMGO was much stronger than morphine after central administration. Co-administration of the peripherally restricted opioid antagonist, naloxone methiodide (NAL-M), significantly attenuated the antinociceptive effects of i.p. DAMGO or morphine. On the other hand, i.c.v. injections of NAL-M partially antagonized the antinociceptive effect of i.p. morphine and failed to affect the antinociceptive action of i.p. DAMGO indicating the partial and pure peripheral antinociceptive effects of morphine and DAMGO, respectively. These results suggest the role of either central or peripheral µ-opioid receptors (MOR) in mediating antinociceptive effects of i.p. µ-opioid agonists in the rat late permanent visceral pain model which closely resembles the clinical situation.


Subject(s)
Analgesics, Opioid/therapeutic use , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Morphine/therapeutic use , Visceral Pain/drug therapy , Acetic Acid/toxicity , Analysis of Variance , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Routes , Drug Interactions , Naloxone/administration & dosage , Naloxone/analogs & derivatives , Narcotic Antagonists/administration & dosage , Quaternary Ammonium Compounds/administration & dosage , Rats , Visceral Pain/chemically induced
14.
Exp Neurol ; 229(2): 502-6, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21458450

ABSTRACT

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.


Subject(s)
Nucleus Accumbens/physiopathology , Pain Perception/physiology , Pain/physiopathology , Receptors, Opioid/metabolism , Analysis of Variance , Animals , Electrodes, Implanted , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Injections, Spinal , Lidocaine/pharmacology , Male , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Pain/drug therapy , Pain/metabolism , Pain Measurement/drug effects , Pain Perception/drug effects , Rats , Rats, Sprague-Dawley , Somatostatin/analogs & derivatives , Somatostatin/pharmacology , Spinal Cord/drug effects , Spinal Cord/metabolism
15.
Neuroscience ; 171(1): 344-50, 2010 Nov 24.
Article in English | MEDLINE | ID: mdl-20736053

ABSTRACT

Sensitization to mechanical stimuli is important in most pain syndromes. We evaluated the populations of nociceptors mediating mechanical hyperalgesia and those mediating mu-opioid receptor (MOR) and delta-opioid receptor (DOR) agonist-induced inhibition of hyperalgesia, in the rat. We found that: (1) intradermal injection of both the endogenous ligand for the Ret receptor, glia-derived growth factor (GDNF), and the ligand for the tropomyosin receptor kinase A (TrkA) receptor, nerve growth factor (NGF)-which are present on distinct populations of nociceptors-both produce mechanical hyperalgesia; (2) DOR agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC) but not MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibit GDNF-induced hyperalgesia; (3) both DAMGO and SNC inhibit NGF hyperalgesia, even in rats pretreated with isolectin B4 (IB4)-saporin, a toxin that destroys IB4-binding neurons; (4) co-administration of low doses of DAMGO and SNC produce enhanced analgesia, and; (5) repeated administration of DAMGO produces cross-tolerance to the analgesic effect of SNC. These findings demonstrate that, most nociceptors have a role in mechanical hyperalgesia, only the DOR agonist inhibits GDNF hyperalgesia, and MOR and DOR are co-localized on a functionally important population of TrkA-positive nociceptors.


Subject(s)
Hyperalgesia/pathology , Nociceptors/metabolism , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Analgesics, Opioid/pharmacology , Analgesics, Opioid/therapeutic use , Animals , Cholera Toxin/metabolism , Cysteine/adverse effects , Cysteine/analogs & derivatives , Disease Models, Animal , Drug Synergism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Horseradish Peroxidase/metabolism , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Male , Pain Threshold/drug effects , Pain Threshold/physiology , Rats , Rats, Sprague-Dawley , S-Nitrosothiols/adverse effects , Vasodilator Agents/adverse effects
16.
Pain ; 148(3): 492-502, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20106595

ABSTRACT

The role of mu-opioid receptors (MORs) in the inflammatory pain processing mechanisms within the ventrobasal complex of the thalamus (VB) is not well understood. This study investigated the effect of modulating MOR activity upon nociception, by stereotaxically injecting specific ligands in the VB. Nociceptive behaviour was evaluated in two established animal models of inflammatory pain, by using the formalin (acute and tonic pain) and the ankle-bend (chronic monoarthritic pain) tests. Control (saline intra-VB injection) formalin-injected rats showed acute and tonic pain-related behaviours. In contrast, intrathalamic administration of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin acetate (DAMGO), a MOR-specific agonist, induced a statistically significant decrease of all tonic phase pain-related behaviours assessed until 30-35min after formalin hind paw injection. In the acute phase only the number of paw-jerks was affected. In monoarthritic rats, there was a noticeable antinociceptive effect with approximately 40min of duration, as denoted by the reduced ankle-bend scores observed after DAMGO injection. Intra-VB injection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP), a specific MOR antagonist, or of CTOP followed, 10min after, by DAMGO had no effects in either formalin or ankle-bend tests. Data show that DAMGO-induced MOR activation in the VB has an antinociceptive effect in the formalin test as well as in chronic pain observed in MA rats, suggesting an important and specific role for MORs in the VB processing of inflammatory pain.


Subject(s)
Inflammation/physiopathology , Pain/physiopathology , Receptors, Opioid, mu/physiology , Ventral Thalamic Nuclei/metabolism , Analgesics, Opioid/pharmacology , Analgesics, Opioid/therapeutic use , Analysis of Variance , Animals , Ankle/innervation , Ankle/physiopathology , Behavior, Animal , Disease Models, Animal , Drug Interactions , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Inflammation/drug therapy , Male , Narcotic Antagonists/pharmacology , Pain/drug therapy , Pain Measurement/drug effects , Pain Measurement/methods , Pain Threshold/drug effects , Rats , Rats, Wistar , Reaction Time/drug effects , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/antagonists & inhibitors , Somatostatin/administration & dosage , Somatostatin/analogs & derivatives , Time Factors , Ventral Thalamic Nuclei/drug effects
17.
Neuropharmacology ; 55(8): 1376-82, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18775732

ABSTRACT

The depression rate of C fibre-evoked spinal field potentials by spinally applied morphine is increased in two states of spinal hyperexcitation, namely the spinal ligation model (SNL) of neuropathic pain and long-term potentiation (LTP) of C fibre-evoked spinal field potentials. This present work sought to determine opioid receptor subtypes involved in such increase in the SNL model. We recorded spinal field potentials during spinal superfusion with increasing, cumulative concentrations of selective subtype-specific agonists in rats subjected to SNL, as well as in non-ligated animals. The mu opioid receptor (MOR) agonist DAMGO significantly depressed field potentials evoked by C (100 nM) or Adelta fibres (1 microM) both in neuropathic and non-ligated rats, whereas the kappa receptor opioid (KOR) agonist +/-U-50488 was ineffective. The delta opioid receptor (DOR) (D-Ala2)-Deltorphin II was more effective in reducing C fibre-evoked spinal field potentials in rats subjected to SNL (100 nM) than in non-ligated rats (100 microM). Subclinical MOR activation (10 nM DAMGO) produced a leftward shift in (D-Ala2)-Deltorphin II dose-response curve in non-ligated rats (IC50 16.59 +/- 0.99 microM vs 120.3 +/- 1.0 microM in the absence of DAMGO), and isobolar analysis revealed synergistic interaction (interaction index 0.25). MOR blockade (100 microM CTOP) disinhibited C fibre-evoked potentials in neuropathic, but not in basal animals, and partially impeded DOR depression in both groups. DOR blockade (1 mM naltrindole) was ineffective in either group. We show that DOR-mediated depression of spinal responses to peripheral unmyelinated fibre-input is increased in the SNL model, an increase that is contributed to by positive interaction with the spinal MOR.


Subject(s)
Evoked Potentials/physiology , Nerve Fibers, Unmyelinated/physiology , Neuralgia/pathology , Neuralgia/physiopathology , Receptors, Opioid, mu/metabolism , Spinal Cord/physiopathology , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/therapeutic use , Analgesics, Non-Narcotic/pharmacology , Analgesics, Non-Narcotic/therapeutic use , Analgesics, Opioid/pharmacology , Analgesics, Opioid/therapeutic use , Animals , Behavior, Animal , Disease Models, Animal , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Evoked Potentials/drug effects , Male , Narcotic Antagonists/pharmacology , Nerve Fibers, Unmyelinated/drug effects , Rats , Rats, Sprague-Dawley , Somatostatin/analogs & derivatives , Somatostatin/pharmacology
18.
Pain Physician ; 11(2 Suppl): S121-32, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18443636

ABSTRACT

Opioids are broad-spectrum analgesics with potent pain-relieving qualities but also with potential adverse effects related to both short-term and long-term therapy. Researchers have attempted to alter existing opioid analgesics, utilize different routes/formulations, or combine opioid analgesics with other compounds in efforts to improve analgesia while minimizing adverse effects. Exogenous opioids, administered in efforts to achieve analgesia, work by mimicking the actions of endogenous opioids. Endogenous opioids and their receptors are located in the brain (supraspinal areas), spinal cord, and periphery. Although opioids and opioid receptors in the brain and spinal cord have received much attention over many years, peripheral endogenous opioid analgesic systems have only been extensively studied during the past decade. It has been known since 1990 that following injection into the rodent hindpaw, D-Ala(2),N-Me-Phe(4), Gly(5)-ol-enkephalin (DAMGO) [a muopioid receptor agonist] probably exerts its antinociceptive effects locally, since the doses administered are too low to have an effect in the central nervous system (CNS). This notion has been supported by the observation that the quaternary compound morphine methyliodide, which does not as readily cross the bloodbrain barrier and enter the CNS, produced antinociception following intradermal administration into the hindpaw, but not when the same dose was administered systemically (subcutaneously at a distant site). With a growing appreciation of peripheral endogenous opioids, peripheral endogenous opioid receptors, and peripheral endogenous opioid analgesic systems, investigators began growing hopeful that it may be possible to achieve adequate analgesics while avoiding unwanted central untoward adverse effects (e.g. respiratory depression, somnolence, addiction). Peripherally-acting opioids, which capitalize on peripheral endogenous opioid analgesic systems, may be one potential future strategy which may be utilized in efforts to achieve potent analgesia with minimal side effects.


Subject(s)
Analgesics, Opioid/therapeutic use , Pain/drug therapy , Peripheral Nervous System/drug effects , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Humans , Inflammation/drug therapy , Leukocytes/drug effects , Leukocytes/physiology , Peripheral Nervous System/physiopathology
19.
Neurosci Lett ; 435(3): 257-62, 2008 Apr 25.
Article in English | MEDLINE | ID: mdl-18359165

ABSTRACT

Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective mu-opioid receptor agonist [d-Ala(2), N-MePhe(4), Gly-ol(5)] enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the beta-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous mu-opioid peptide beta-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of mu-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.


Subject(s)
Morphine/administration & dosage , Narcotics/administration & dosage , Reward , Sciatica/drug therapy , Sciatica/psychology , beta-Endorphin/physiology , Analysis of Variance , Animals , Behavior, Animal/drug effects , Conditioning, Operant/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Female , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Male , Mice , Mice, Knockout , Pain Measurement , Protein Binding/drug effects , Reaction Time/drug effects , Sciatica/genetics , Time Factors , Tyrosine 3-Monooxygenase/metabolism , beta-Endorphin/deficiency
20.
Int J Urol ; 14(3): 226-31; discussion 232, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17430260

ABSTRACT

AIM: In order to determine the influence of different opioid receptor subtypes on detrusor overactivity after left middle cerebral artery (MCA) occlusion, cystometric recordings were obtained in conscious rats. METHODS: Female Sprague-Dawley rats were used in this study. Control cystometrography was followed by left MCA occlusion. The sham-operated (SO) rats underwent the same procedures except for MCA occlusion. [D-Ala(2), Phe(4), Gly(5)]-enkephalin (DAGO; mu-opioid agonist), [D-Pen(2,5)]-enkephalin (DPDPE; delta1-opioid agonist), deltorpin II (delta2-opioid agonist), and U-50488 (kappa-opioid agonist) were administered intracerebroventricularly at graded doses. The bladder capacity, residual volume, micturition threshold pressure, and bladder contraction pressure were determined. Finally, the volume of the infarction was measured. RESULTS: The intracerebroventricular administration of DAGO and DPDPE significantly increased the bladder capacity in the cerebrally infarcted (CI) and SO rats, but differences in the changes in bladder capacity between the CI and SO rats were not significant. Deltorpin II did not produce any changes in the bladder capacity in the CI or SO rats at any dose examined. However, the intracerebroventricular administration of U-50488 significantly increased the bladder capacity in the CI rats but not in the SO rats. None of the drugs affected the residual volume, micturition threshold pressure or bladder contraction pressure at any dosage examined. The mean infarcted volumes were not significantly different from those in the vehicle-treated rats. CONCLUSION: These results suggest that the opioid receptor subtypes, mu and delta1 in the brain, are related to the micturition reflex. Furthermore, the kappa opioid agonist might be useful for the suppression of detrusor overactivity caused by cerebral infarction.


Subject(s)
Analgesics, Non-Narcotic/therapeutic use , Analgesics, Opioid/therapeutic use , Cerebral Infarction/physiopathology , Enkephalin, D-Penicillamine (2,5)-/therapeutic use , Urinary Bladder, Overactive/drug therapy , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/administration & dosage , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/therapeutic use , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Opioid/administration & dosage , Animals , Cerebral Infarction/complications , Cerebral Ventricles , Disease Models, Animal , Drug Administration Routes , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/administration & dosage , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Enkephalin, D-Penicillamine (2,5)-/administration & dosage , Female , Oligopeptides/administration & dosage , Oligopeptides/therapeutic use , Rats , Rats, Sprague-Dawley , Treatment Outcome , Urinary Bladder, Overactive/etiology , Urinary Bladder, Overactive/physiopathology , Urodynamics/drug effects
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