u-50488 and Chronic-Disease

The amygdala plays an important role in the processing of chronic pain and pain memory formation. Particularly, it is involved in the emotional and affective components of the pain circuitry. The role of kappa opioid receptors in these pain conditions is only partly known. The present study investigates the effect of kappa receptor activation on synaptic transmission and synaptic plasticity in the amygdala.. Electrophysiological in vitro experiments were carried out in brain slices of male C57BL/6JOlaHsd mice. The effect of the kappa opioid receptor agonist U50,488H (5 microM) and the selective kappa opioid receptor antagonist nor-BNI (3 microM) on field potential (FP) amplitude and the induction of long-term potentiation (LTP) in the basolateral amygdala (BLA) was examined.. High frequency stimulation (HFS) of afferents in the lateral amygdala with two trains of 100 pulses at 50 Hz increased the FP amplitudes to 119+/-2% (mean+/-SEM; n=6) in the BLA. U50,488H decreased synaptic transmission (baseline: 100+/-0.5%; U50,488H: 86.3+/-2.4%; n=6) and blocked the induction of LTP (U50,488H: 100+/-4.1%; HFS: 102.6+/-7%; n=6). The effect on synaptic transmission and on LTP was completely reversed or prevented by application of nor-BNI, which itself had no effect on synaptic transmission or the induction of LTP.. Kappa opioid receptor activation decreases synaptic transmission and inhibits the induction of LTP in the BLA of the mouse. These findings may be associated with the effects of kappa opioid agonists in chronic pain and pain memory formation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amygdala; Analgesics, Non-Narcotic; Animals; Chronic Disease; Electric Stimulation; Electrophysiology; Emotions; Extinction, Psychological; Long-Term Potentiation; Male; Mice; Mice, Inbred C57BL; Naltrexone; Pain; Receptors, Opioid, kappa; Synaptic Transmission

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

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

In this study, we determined the effect of U50,488H (a selective kappa-opioid receptor agonist) on pulmonary artery in rats and investigated its prevention and treatment effects on hypoxic pulmonary hypertension (HPH). Isolated pulmonary arterial rings were superfused and the tension of the vessel was measured. The model of HPH was developed and indexes for hemodynamics and right ventricular hypertrophy were measured. We found that U50,488H relaxed the pulmonary artery rings in a dose-dependent manner and the effect was abolished by nor-binaltorphimine, a selective kappa-opioid receptor antagonist. Intravenous administration of U50,488H significantly lowered mean pulmonary artery pressure (mPAP) in normal rats and this effect was also abolished by nor-binaltorphimine. Hypoxia induced severe HPH in rats and intraperitoneal administration of U50,488H (every other day) during chronic hypoxia reduced mPAP and attenuated right ventricular hypertrophy compared with the control group. Moreover, acute intravenous administration of U50,488H after the rats subjected to chronic hypoxia for 4 weeks significantly lowered mPAP. Thus, U50,488H has significant vasorelaxant effect in rat pulmonary artery and has certain preventive and therapeutic application in HPH.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Blood Pressure; Chronic Disease; Dose-Response Relationship, Drug; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Injections, Intravenous; Male; Perfusion; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley

Opioids are commonly used for pain relief clinically and reduce hyperalgesia in most animal models. Two injections of acidic saline into one gastrocnemius muscle 5 days apart produce a long-lasting bilateral hyperalgesia without associated tissue damage. The current study was undertaken to assess the effects of opioid agonists on mechanical hyperalgesia induced by repeated intramuscular injections of acid. Morphine (mu-agonist), [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (mu-agonist; DAMGO), 4-[((alpha)R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (delta-agonist; SNC80), or (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cylcohexyl]-benzeneacetamide hydrochloride (kappa-agonist; U50,488) were administered intrathecally to activate opioid receptors once hyperalgesia was developed. Mechanical hyperalgesia was assessed by measuring the withdrawal thresholds to mechanical stimuli (von Frey filaments) before the first and second intramuscular injection, 24 h after the second intramuscular injection, and for 1 h after administration of the opioid agonist or vehicle. Morphine, DAMGO, and SNC80 dose dependently increased the mechanical withdrawal threshold back toward baseline responses. The reduction in hyperalgesia produced by morphine and DAMGO was prevented by H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) and that of SNC80 was prevented by naltrindole. U50,488 had no effect on the decreased mechanical withdrawal thresholds. Thus, activation of mu- and delta-, but not kappa-, opioid receptors in the spinal cord reduces mechanical hyperalgesia following repeated intramuscular injection of acid, thus validating the use of this new model of chronic muscle pain.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Behavior, Animal; Benzamides; Chronic Disease; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hydrochloric Acid; Hydrogen-Ion Concentration; Hyperalgesia; Injections, Spinal; Morphine; Muscular Diseases; Pain Threshold; Physical Stimulation; Piperazines; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

kappa-Opioid receptor (kappa-OR) stimulation with U50,488H, a selective kappa-OR agonist, or activation of protein kinase C (PKC) with 4-phorbol 12-myristate 13-acetate (PMA), an activator of PKC, decreased the electrically induced intracellular Ca(2+) ([Ca(2+)](i)) transient and increased the intracellular pH (pH(i)) in single ventricular myocytes of rats subjected to 10% oxygen for 4 wk. The effects of U50,488H were abolished by nor-binaltorphimine, a selective kappa-OR antagonist, and calphostin C, a specific inhibitor of PKC, while the effects of PMA were abolished by calphostin C and ethylisopropylamiloride (EIPA), a potent Na(+)/H(+) exchange blocker. In both right hypertrophied and left nonhypertrophied ventricles of chronically hypoxic rats, the effects of U50,488H or PMA on [Ca(2+)](i) transient and pH(i) were significantly attenuated and completely abolished, respectively. Results are first evidence that the [Ca(2+)](i) and pH(i) responses to kappa-OR stimulation are attenuated in the chronically hypoxic rat heart, which may be due to reduced responses to PKC activation. Responses to all treatments were the same for right and left ventricles, indicating that the functional impairment is independent of hypertrophy. kappa-OR mRNA expression was the same in right and left ventricles of both normoxic and hypoxic rats, indicating no regional specificity.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Calcium; Chronic Disease; Electric Stimulation; Heart Ventricles; Hydrogen-Ion Concentration; Hypoxia; Intracellular Membranes; Male; Myocardial Contraction; Myocardium; Osmolar Concentration; Protons; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; RNA, Messenger; Tetradecanoylphorbol Acetate

We examined the effects of intrathecal (i.t.) selective opioid receptor agonists in alleviating mechanical and cold allodynia in spinally injured rats. Both DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-opioid receptor agonist) and DPDPE ([D-Phe2,D-Phe5]-enkephalin, a delta-opioid receptor agonist) dose-dependently relieved the chronic allodynia-like behavior at doses selective for their respective receptors. The anti-allodynic effect of DAMGO and DPDPE was reversed by the selective mu- and delta-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and naltrindole, respectively. In contrast, the selective kappa-opioid receptor agonist U50488H did not alleviate the allodynia-like behavior, but rather enhanced it. The anti-nociceptive and anti-allodynic effect of i.t. DAMGO was blocked by U50488H. Thus, activation of spinal mu- and delta-, but not kappa-opioid receptors produced anti-allodynic effect in this model of central pain. Drugs which act selectively on opioid receptor subtypes may be useful in managing chronic central pain of spinal cord origin.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Behavior, Animal; Chronic Disease; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Female; Hypesthesia; Injections, Spinal; Nociceptors; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Spinal Cord Injuries

1. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (kappa)-opioid, U-50,488H (trans-(+/-)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]- benzene-acetamide methane sulphonate), possesses anti-arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, kappa-opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti-arthritic effects in the periphery. Thus, the dose-effect relationship of a kappa-opioid agonist, U-50,488H was compared after both local and distant administration. Further, we tested whether the anti-arthritic effects of this drug are stereospecific and receptor-mediated by use of opioid antagonists. 2. Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (+/-)-U-50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (+/-)-U-50,488H on radiology and histology varied according to treatment time. Administration of (+/-)-U-50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (+/-)-U-50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose-dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (+/-)-U-50,488H was approximately fourfold more potent as an 'anti-arthritic' agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 +/- 1.6 vs 19.5 +/- 0.8 mg kg-1). 3. Equivalent doses of the (-)-enantiomer (20 mg kg-1day-1) and the racemate (+/-) of U-50,488H (40 mg kg-1day-1), elicited a similar attenuation of arthritic parameters while the (+/-)-enantiomer exacerbated arthritis, suggesting that the anti-arthritic activity lies solely with the (-)-enantiomer. 4. Both the peripherally selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266 ((-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan), were

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Arthritis, Experimental; Benzomorphans; Chronic Disease; Dose-Response Relationship, Drug; Hindlimb; Male; Mycobacterium; Naloxone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Lew; Receptors, Opioid, kappa; Stereoisomerism; Time Factors