u-50488 and Acute-Disease

In the present work the effect of papaverine, a non specific smooth muscle relaxant, was investigated on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum in vitro. Furthermore, the effect of papaverine was also considered on DAGO (highly selective mu -agonist) and U50-488H (highly selective k-agonist) withdrawal to test whether the possible interaction of papaverine on opioid withdrawal involves mu - and/or k-opioid receptors. Following a 4 min in vitro exposure to opioid agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. Papaverine treatment (1 x 10(-7) - 5 x 10(-7) - 1 x 10(-6) M) before or after the opioid agonists was able of both preventing and reversing the naloxone-induced contracture after exposure to mu (morphine and DAGO) or k (U50-488H) opiate agonists in a concentration-dependent fascion. Both acetylcholine response and electrical stimulation were not affected by papaverine treatment whereas the final opiate withdrawal was still reduced. The results of the present study indicate that papaverine was able to produce significative influence on the opiate withdrawal in vitro and papaverine was able to exert its effect both at mu and k opioid agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acute Disease; Animals; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Guinea Pigs; Ileum; Male; Morphine; Muscle Contraction; Muscle, Smooth; Narcotic Antagonists; Papaverine; Parasympatholytics; Phytotherapy; Plants, Medicinal; Receptors, Opioid; Substance Withdrawal Syndrome

1. The anti-nociceptive effects of contralateral administration of kappa-opioid agonist U-50,488H were investigated in rats. 2. Inflammation was induced by unilateral injection of 1% carrageenan into the right hindpaw. Prior to carrageenan injection, U-50,488H or saline was administered into the left hindpaw. Withdrawal responses to mechanical and heat stimulation and oedema levels were evaluated at 3, 6 and 24 h post-carrageenan injection. 3. The results showed that the inflammatory effect of 1% carrageenan peaked after 6 h with bilateral decreases in withdrawal latencies and ipsilateral oedema formation. 4. Contralateral treatment with 0.01, 0.05, 0.3 and 2 mg of U-50,488H attenuated nociceptive reflexes to mechanical stimulation on the inflamed side at 6 h. The anti-nociceptive effect of contralateral treatment was dose-dependent at 3 and 24 h. The hindpaw withdrawal latencies to heat stimulation were prolonged at 3 and 24 h after contralateral treatment with 0.3 mg U-50,488H. No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U-50,488H. 5. Sciatic nerve denervation on the contralateral side abolished the anti-nociceptive effects of U-50,488H (0.3 and 2 mg). In contrast, contralateral injection of 1 mg morphine prolonged paw latencies in denervated rats. 6. Both co-administration of the peripherally selective opioid antagonist naloxone methiodide with 0.3 mg U-50,488H, and alternatively, systemic administration of 0.3 mg U-50,488H reversed the anti-nociceptive effects induced by contralateral injection of U-50,488H. 7. Taken together, our findings indicate that the contralateral administration of U-50,488H attenuates nociceptive behaviour resulting from acute inflammation. The effect is mediated via peripheral neuronal kappa-opioid receptors and, possibly, spinal cord mechanisms, suggesting a new treatment approach for acute inflammatory conditions.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acute Disease; Analgesics, Opioid; Animals; Behavior, Animal; Denervation; Hindlimb; Hot Temperature; Inflammation; Male; Naloxone; Pain; Pain Measurement; Physical Stimulation; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sciatic Nerve

Opioids may play an immunomodulatory role in the pathogenesis of human immunodeficiency virus-1 (HIV-1) infection. Recently, synthetic kappa-opioid receptor (KOR) ligands have been found to have anti-human immunodeficiency virus type 1 activity in acutely infected brain macrophages. In the present study, we investigated whether the selective KOR ligand U50488 would exert such an anti-HIV-1 effect in acutely infected blood monocyte-derived macrophages (MDM). Treatment of acutely infected MDM with U50488 induced a concentration-dependent inhibition of HIV-1 expression. The dose--response relationship of U50488 was U-shaped with a peak effect observed at 10(-13) M, which was evident at both 7 and 14 days post-infection. The KOR antagonist nor-binaltorphimine blocked the anti-HIV-1 effect of U50488 by 73%, indicating involvement of a KOR-mediated mechanism. Also, expression of KOR mRNA and binding activity with a fluorescence-labeled KOR ligand supported the existence of KOR on MDM. Antibodies to the beta-chemokine, RANTES (regulated on activation normal T-cell expressed and secreted), but not to various other cytokines, blocked U50488 inhibition by 56% suggesting that the anti-HIV-1 effect of U50488 involved, in part, the production of RANTES by MDM. Taken together, these in vitro findings support the anti-HIV-1 property of U50488, and suggest that KOR ligands may have therapeutic potential for treating patients with acquired immunodeficiency syndrome.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acquired Immunodeficiency Syndrome; Acute Disease; Analgesics, Non-Narcotic; Cells, Cultured; Chemokine CCL5; Cytokines; Dose-Response Relationship, Drug; Fluorescence; HIV-1; Humans; Macrophages; Monocytes; Receptors, Opioid, kappa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Subcutaneous injection of the potent, nonselective opioid antagonist diprenorphine inhibits the vasopressin response to acute hypovolemia. To determine if this inhibition is due to antagonism of opioid receptors in brain pathways that mediate volume control, we determined the vasopressin response to different stimuli when diprenorphine or other opiates were injected into the cerebral ventricles, the nucleus tractus solitarius (NTS), or the lateral parabrachial nucleus (PBN) of rats. We found that the vasopressin response to hypovolemia was inhibited by injection of diprenorphine into the cerebral ventricles at a dose too low to be effective when given subcutaneously. This response also was inhibited when a 20-fold lower dose of diprenorphine was injected into the PBN but not when it was injected into the NTS. The inhibitory effect of diprenorphine in the PBN was not attributable to a decrease in osmotic or hypovolemic stimulation and did not occur with osmotic or hypotensive stimuli. Injecting the PBN with equimolar doses of the mu antagonist naloxone, the delta antagonist ICI-154,129 or the kappa-1 agonist U-50,488H had no effect on basal or volume-stimulated vasopressin. We conclude that the inhibition of vasopressin by diprenorphine is due partially to action at a novel class of opioid receptors that transmit volume stimuli through the PBN.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acute Disease; Animals; Antihypertensive Agents; Brain; Cerebral Ventricles; Diprenorphine; Enkephalin, Leucine; Hemodynamics; Male; Naloxone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Sprague-Dawley; Shock; Solitary Nucleus; Stimulation, Chemical; Vasopressins