naloxone and senktide

Effects of two commonly used tachykinin NK-3 receptor antagonists (SR 142801 and R820) intrathecally (i.t.) administered were assessed in the rat tail-flick test. SR142801 and its (R)-enantiomer SR142806 (1.3, 6.5 and 65 nmol) were found as potent as senktide and [MePhe7]NKB (NK-3 selective agonists) to induce transient antinociceptive effects. Naloxone (10 microg) and R820 (6.5 nmol) blocked reversibly the responses to 6.5 nmol senktide, [MePhe7]NKB, SR142801 and SR142806 when administered i.t. 15 min earlier. However, the antinociceptive responses induced by SR142801 and SR142806 were not affected by i.t. pretreatments with NK-1 (6.5 nmol SR140333) and NK-2 (6.5 nmol SR48968) receptor antagonists. In control experiments, the NK-1 and NK-2 antagonists prevented the hyperalgesic effects to NK-1 ([Sar9,Met(O2)11]SP) and NK-2 ([beta-Ala8] NKA(4-10)) receptor agonists (6.5 nmol i.t.), respectively. R820 had no direct effect on nociceptive threshold and failed to alter angiotensin II-induced antinociception. The data suggest that the antinociceptive effect of SR142801 is due to an agonist effect at NK-3 receptor in the rat spinal cord that involves a local opioid mechanism. These results can be best explained by the existence of inter-species NK-3 receptor subtypes.

Topics: Analgesics; Animals; Drug Interactions; Indoles; Male; Naloxone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Oligopeptides; Pain Measurement; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Spinal Cord; Substance P

The present study was designed to clarify whether opioid neuronal systems are involved in the beneficial effects of tachykinins such as the neurokinin NK1 receptor agonist, substance P (SP), the neurokinin NK2 receptor agonist, neurokinin A (NKA), and the neurokinin NK3 receptor agonist, senktide, on the scopolamine-induced impairment of spontaneous alternation performance in mice. Intracerebroventricular injections of SP (0.1 microgram), NKA (0.3 microgram) and senktide (3 ng) inhibited the scopolamine (1 mg/kg)-induced impairment of spontaneous alternation performance without influencing total arm entries, indicating the antiamnesic effects of tachykinins. Furthermore, the inhibitory effects of SP, but not those of NKA or senktide, were almost completely reversed by pretreatment with naloxone (1 mg/kg). However, the effects of SP on the scopolamine-induced impairment of spontaneous alternation performance were not influenced by pretreatment with the mu-opioid receptor antagonist, beta-funaltrexamine (5 micrograms), the delta-opioid receptor antagonist, naltrindole (4 ng), and the kappa-opioid receptor antagonist, nor-binaltorphimine (4 micrograms). These findings suggest that the effects of SP, unlike those of NKA or senktide, on the scopolamine-induced impairment of spontaneous alternation performance associated with spatial working memory are not mediated simply via a single type of opioid receptors, such as mu, delta or kappa.

Topics: Animals; Male; Mice; Muscarinic Antagonists; Naloxone; Naltrexone; Narcotic Antagonists; Neurokinin A; Peptide Fragments; Psychomotor Performance; Scopolamine; Substance P; Tachykinins

Recently, two compounds have been developed, designated septide and senktide, which are highly selective agonists for the substance P receptor, types NK-1 and NK-3, respectively. Each of these, when injected intrathecally in awake rats, produced a distinct and non-overlapping constellation of sensory and behavioural effects which were subsets of the symptoms evoked by intrathecal administration of substance P. Prior systemic administration of 5-hydroxytryptamine (5-HT), alpha-adrenergic and opiate receptor antagonists, at doses sufficient to block the behavioural effects of the corresponding receptor agonists, did not alter responses to intrathecally injected septide or senktide. This was so, even for symptoms which suggested inhibitory mediation, hypoalgesia and (transient) motor flaccidity. Septide and senktide, administered by lumbar puncture and by indwelling catheter, produced identical results. Finally, in contrast to some other peptides, flaccid paralysis induced by senktide was not accompanied by spinal necrosis.

Topics: Animals; Injections, Spinal; Male; Methysergide; Morphine; Muscles; Naloxone; Pain; Peptide Fragments; Phentolamine; Phenylephrine; Posture; Rats; Rats, Inbred Strains; Serotonin; Spinal Cord; Stereotyped Behavior; Substance P