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The administration of kappa-opioid receptor antagonists, nor-binaltorphimine (norBNI) and 5'-guanidinonaltrindole (GNTI) enhanced allodynia in rats and mice after sciatic nerve ligation. In order to understand the mechanism underlying this effect, we examined the possible involvement of the endogenous ligand of kappa-opioid receptor dynorphin. The experiments were carried out on male Wistar rats and on Albino-Swiss mice. The rats had been implanted with a catheter 7 days earlier in the subarachnoid space of the spinal cord. Intrathecal (i.t.) administrations in mice were made by lumbar puncture. The animals were i.t. injected with norBNI, GNTI (kappa-opioid receptor antagonists), dynorphin A1-17 antiserum (DYN A/S), ketamine (NMDA receptor antagonist) and their combinations. The nociceptive sensitivity was assessed using the mechanical (von Frey) and thermal allodynia tests on days 2-4 and 8-10 after the sciatic nerve ligation. Both antagonists, norBNI and GNTI, significantly enhanced mechanical and thermal allodynia in rats and mice with neuropathic pain. The potentiation of allodynia after the administration of norBNI or GNTI was inhibited by earlier administration of DYN A/S or by ketamine. Our results suggest that allodynia is mediated through nonopioid effect of the endogenous opioid peptide, dynorphin. The nonopioid action is potentiated by the blockade of kappa-opioid receptors, and corresponding to the elevation of prodynorphin mRNA level in neuropathic pain. Furthermore, the potentiation of allodynia after the administration of the above drugs appears to be mediated through the activation of NMDA receptors directly by dynorphin.

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.

Contains fulltext : 28629.pdf (Publisher’s version ) (Open Access) Numerous studies have provided evidence for the involvement of opioids in the mechanisms of various forms of epilepsy. Most have investigated the effects of opioids in the control and genesis of convulsive epilepsy, whereas data on opioids mechanisms with respect to nonconvulsive epilepsy are almost lacking. Therefore, we investigated the role of the opioid subsystems in WAG/Rij rats, a genetic rat model of human absence epilepsy. Six-month-old male WAG/Rij were chronically provided with EEG electrodes and some with cannulas in the lateral ventricle. The baseline EEG was measured, and the drugs or solvent was injected. The EEG was recorded for 1 h, and the number and duration of spike-wave discharges (SWD) was counted. SWD were facilitated by the nonspecific opioid antagonist naloxone (intraperitoneally), suggesting that SWD are tonically inhibited by the endogenous opioid system. Next, specific mu, delta and kappa agonists and antagonists were evaluated. The mu receptor agonist DAMGO increased (intracerebroventricularly, i.c.v.) markedly the number of SWD, whereas DPDPE, a delta receptor agonist, had no effect. Three kappa agonists (i.c.v. or subcutaneously) US0488H, U69593, or PDI 17301 dosedependently inhibited the number of SWD. These effects could be antagonized by the kappa antagonist Nor-BNI. Nor-BN1 itself enhanced the number of SWD, but the mu antagonist naltrindole had no effect. Endogenous opioids, which act through the kappa receptors, tonically control the initiation of SWD. Kappa agonists, if devoid of psychomimetic effects, might be useful antiabsence drugs.