enkephalin--ala(2)-mephe(4)-gly(5)- and cyprodime

The stimulation of peripheral opioid receptors yields analgesic responses in a model of bone cancer-induced pain in mice. In order to know the type(s) of peripheral opiate receptors involved, the paw thermal withdrawal latencies were measured in C3H/HeJ mice bearing a tibial osteosarcoma, after administering selective agonists of mu-,delta-and kappa-opiate receptors. The peritumoral administration of DAGO (0.6-6 microg) inhibited the osteosarcoma-induced hyperalgesia at doses ineffective in healthy animals, the highest one even increasing the withdrawal latencies over the control values. Naloxone-methiodide (2 mg/kg) and cyprodime (1 mg/kg), but not naltrindole (0.1 mg/kg) nor nor-binaltorphimine (10 mg/kg), antagonized DAGO-induced analgesic effects, these therefore probably being mediated through peripheral mu-opioid receptors. The peritumoral injection of DPDPE (100 microg) induced analgesia which was inhibited by naloxone-methiodide and naltrindole but not by nor-binaltorphimine. Cyprodime partially antagonized the analgesia induced by 100 microg of DPDPE, but did not modify the effect induced by 30 microg of this agonist-a dose that restores the hyperalgesic latencies up to the control values. The antihyperalgesic effect induced by the peritumoral administration of U-50,488H (1 microg) was antagonized by naloxone-methiodide and nor-binaltorphimine, but not by cyprodime nor naltrindole, thus suggesting the involvement of peripheral kappa-opioid receptors. In conclusion, the stimulation of peripheral mu-, delta- and kappa-opioid receptors is a pharmacological strategy useful for relieving this experimental type of bone cancer-induced pain, the greatest analgesic effect being achieved by stimulating peripheral mu-opioid receptors.

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hyperalgesia; Mice; Morphinans; Naltrexone; Narcotic Antagonists; Osteosarcoma; Receptors, Opioid

Co-localization of opioid and melanocortin receptor expression, especially at the spinal cord level in the dorsal horn and in the gray matter surrounding the central canal led to the suggestion that melanocortins might play a role in nociceptive processes. In the present studies, we aimed to determine the effects of melanocortins, administered intrathecally, on allodynia, and to ascertain whether there is an interaction between opioid and melanocortin systems at the spinal cord level. Neuropathic pain was induced by chronic constriction injury (CCI) of the right sciatic nerve in rats. Tactile allodynia was assessed using von Frey filaments, while thermal hyperlagesia was evaluated in cold water allodynia test. In the present experiments, melanocortin receptor antagonist, SHU9119 was much more potent than mu-opioid receptor agonist, morphine after their intrathecal (i.th.) administration in neuropathic rats. SHU9119 alleviated allodynia in a comparable manner to DAMGO, a selective and potent mu-opioid receptor agonist. Administration of melanocortin receptor agonist, melanotan-II (MTII) increased the sensitivity to tactile and cold stimulation. Moreover, we demonstrated that the selective blockade of mu-opioid receptor by cyprodime (CP) enhanced antiallodynic effect of SHU9119 as well as pronociceptive action of MTII, whereas the combined administration of mu receptor agonist (DAMGO) and SHU9119 significantly reduced the analgesic effect of those ligands. DAMGO also reversed the proallodynic effect of melanocortin receptor agonist, MTII. In conclusion, it seems that the endogenous opioidergic system acts as a functional antagonist of melanocortinergic system, and mu-opioid receptor activity appears to be involved in the modulation of melanocortin system function.

Topics: alpha-MSH; Analgesics, Opioid; Animals; Chronic Disease; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Spinal; Male; Melanocyte-Stimulating Hormones; Morphinans; Morphine; Nociceptors; Oligopeptides; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Opioid, mu; Sciatica; Spinal Cord

Relationship between activation of opioid receptors and muscarinic autoinhibition in acetylcholine (ACh) release from the myenteric plexus was studied in longitudinal muscle myenteric plexus (LMMP) preparations of guinea pig ileum. A mu-receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol] enkephalin (DAMGO), at a concentration of 1 microM inhibited the ACh release evoked by electrical field stimulation (EFS) at 1 Hz but not at 10 Hz. After the muscarinic autoreceptors were blocked with atropine (1 microM), DAMGO inhibited EFS-evoked ACh release also at 10 Hz. After the autoreceptors were potently activated with muscarine (200 microM), the inhibitory effect of DAMGO at 1 Hz was abolished. A kappa-receptor agonist, U-50,488, at 1 microM inhibited the EFS-evoked ACh release both at 1 and 10 Hz. U-50,488 inhibited ACh release regardless of the presence of atropine or muscarine. A delta-agonist, enkephalin [D-PEN2.5] (PDPDE), did not show any significant effect. On the other hand, a selective mu-receptor antagonist, cyprodime, increased ACh release evoked by EFS at 1 Hz, but not at 10 Hz. After the autoreceptors were blocked, cyprodime increased EFS-evoked ACh release also at 10 Hz. The selective kappa-receptor antagonist, nor-binaltorphimine, did not affect ACh release in the absence or presence of atropine. The results suggest that endogenous opioid(s) inhibits ACh release by activating mu-, but not kappa- and delta-receptors in the LMMP of guinea pig ileum and that the inhibitory effect of endogenous opioid(s) in the ACh release is important when muscarinic autoinhibition mechanism does not fully work.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetylcholine; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Atropine; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphinans; Muscarine; Muscarinic Agonists; Muscarinic Antagonists; Muscle, Smooth; Myenteric Plexus; Naltrexone; Narcotic Antagonists; Opioid Peptides; Receptors, Muscarinic; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

The PNS was anticipated to be involved in the modulation of immune responses. To study aspects of this neuronal-immune communication, a recently developed tissue slice method was used to study the effects of adrenergic and opioidergic transmitters on interleukin 6 (IL-6) secretion in the spleen. The alpha 2-adrenergic agonist p-aminoclonidine (10(-7) M) inhibited IL-6 secretion (control vs. p-aminoclonidine, 100.0 +/- 4.76 vs. 59.3 +/- 6.6% of control values; p < 0.001). The alpha 1-adrenergic agonist methoxamine (10(-8) M) also inhibited IL-6 secretion (100.0 +/- 4.8 vs. 71.5 +/- 3.8%; p < 0.001). The endogenous opioids beta-endorphin (10(-10) M), methionine-enkephalin (10(-9) M), and leucine-enkephalin (10(-9) M) inhibited IL-6 secretion as well (p = 0.0051, p = 0.0337, and p = 0.0226, respectively). Electrical stimulation of spleen slices inhibited IL-6 secretion (100.0 +/- 4.3 vs. 56.7 +/- 4.6% of control values; p < 0.001). The involvement of alpha-adrenergic and opioidergic molecules in this electrically induced inhibition was shown by the use of antagonists. Electrical inhibition of IL-6 secretion was attenuated by phentolamine (10(-7) M; p = 0.0345), by naloxone (10(-6) M; p = 0.0046), by cyprodime (10(-8) M; p = 0.0014), and by the combination of cyprodime (10(-7) M) plus phentolamine (10(-8) M; p < 0.0001). We conclude from the complementary studies that the inhibition of IL-6 secretion induced by electrical pulses was mostly mediated by alpha-adrenergic and mu-opioidergic endogenous transmitters.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Analgesics; Animals; beta-Endorphin; Clonidine; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Methionine; Enkephalins; Female; Interleukin-6; Isoproterenol; Mice; Mice, Inbred Strains; Morphinans; Naloxone; Narcotic Antagonists; Neurons; Phentolamine; Propranolol; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, Opioid; Spleen