apelin-13-peptide and Pain

Apelin-13 is an endogenous peptide with potential analgesic action, although the sites of its analgesic effects remain uncertain and the results are even controversial with regard to its pain modulating action. This study evaluated the possible pain-modulating action of peripherally administered apelin-13 using heat-induced, withdrawal latency to the thermal stimuli, acute pain model in mice. Involvement of peripheral mechanisms was tested, by using the intracellular calcium concentrations as a key signal for nociceptive transmission, in cultured rat dorsal root ganglion (DRG) neurons.. DRG neurons were cultured on glass coverslips following enzymatic digestion and mechanical agitation, and loaded with the calcium-sensitive dye Fura-2 acetoxymethyl ester (1 µM). Intracellular calcium responses in individual DRG neurons were quantified by ratiometric calcium imaging technique.. Peripheral injection of a single dose of apelin-13 (100 mg/kg and 300 mg/kg) significantly decreases the latency to painful stimuli in a dose and time-dependent manner (p < 0.01, p < 0.05, respectively, n = 8 each). Apelin-13 (0.1 µM and 1 µM) did not produce a significant effect on cytoplasmic Ca(2+) ([Ca(2+)](i)) responses, evoked by membrane depolarization, in cultured rat DRG neurons.. Together these results indicate that apelin-13 can cause increased pain sensitivity after peripheral administration, but this effect does not involve calcium mediated signaling in primary sensory neurons.

Topics: Animals; Calcium Signaling; Disease Models, Animal; Fluorescence; Ganglia, Spinal; Hot Temperature; Injections, Intraperitoneal; Intercellular Signaling Peptides and Proteins; Male; Mice, Inbred BALB C; Nociception; Pain; Pain Threshold; Potassium Chloride; Rats, Wistar; Sensory Receptor Cells; Signal Transduction

Pain represents a major contributing factor to the individual's quality of life. Although pain killers as opioids, endogenous or exogenous peptides can decrease pain perception, the chronic use of them leads to antinociceptive tolerance. It has been demonstrated that neuropeptide apelin has potent antinoceptive effect. However, the possibility of the induction of its antinociceptive tolerance has not yet been clarified. The tail-flick test was used to assess the nociceptive threshold. All experiments were carried out on male Wistar rats which received intrathecal apelin for 7days. To determine the role of apelin and opioid receptors on the development of apelin analgesic tolerance, their receptor antagonists (F-13 A and naloxone, respectively) were injected simultaneously with apelin. The lumbar spinal cord was assayed to determine apelin receptor levels by the western blotting method. Plasma corticosterone levels were assayed using ELISA. Results showed that apelin (3μg/rat) induced strong thermal antinociception. In addition, chronic apelin produced tolerance to its antinociceptive effect and down regulated spinal apelin receptor. F-13 A and naloxone could inhibit apelin tolerance development. The corticosterone levels did not change following drug administration. Taken together, the data indicated that apelin like other analgesic drugs leads to the induction of side effects such as analgesic tolerance which is mediated partly via the apelin and opioid receptors activation.

Topics: Animals; Apelin Receptors; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Spinal; Intercellular Signaling Peptides and Proteins; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Opioid; Spinal Cord

Apelin was identified as natural ligand for APJ, a G protein-coupled receptor. APJ is expressed in spinal cord and dorsal root ganglion. This study was designed to investigate the effects and mechanisms of intrathecally (i.t.) administered apelin-13 on nociceptive response in formalin test and tail-flick test. In formalin test, i.t. injection of apelin-13 (0.3-3 nmol/mouse) had no effect on the nociceptive response in either acute phase (0-10 min) or interphase (10-20 min), but significantly produced hyperalgesic effect in late phase (20-30 min) at the dose of 3 nmol/mouse. The APJ receptor antagonist apelin-13(F13A) and GABAA receptor antagonist bicuculline methiodide, but not opioid receptor antagonist naloxone, significantly blocked the hyperalgesia caused by apelin-13 in late phase, indicating that i.t. apelin-13- induced hyperalgesia was mediated by APJ and GABAA receptor, rather than opioid receptor. However, in tail-flick test, i.t. injected apelin-13 (1 and 3 nmol/mouse) induced a significant antinociceptive effect, which was significantly antagonized by apelin-13(F13A) and naloxone, suggesting APJ and opioid receptor were involved in the antinociception of spinal apelin-13.

Topics: Amino Acid Sequence; Animals; Apelin Receptors; Injections, Spinal; Intercellular Signaling Peptides and Proteins; Male; Mice; Molecular Sequence Data; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, G-Protein-Coupled; Receptors, Opioid; Spinal Cord

The effect of apelin-13 on pain modulation at the supraspinal level was investigated in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of apelin-13 (0.3, 0.5, 0.8 and 3 microg/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the APJ receptor antagonist apelin-13(F13A), indicating an APJ receptor-mediated mechanism. Furthermore, naloxone, beta-funaltrexamine and naloxonazine, could reverse the analgesic effect. However, naltrindole or nor-binaltorphimine could not reverse the effect, suggesting that mu opioid receptor (primarily mu(1) opioid receptor subtype) is involved in the analgesic response evoked by apelin-13. Moreover, i.c.v. administration of apelin-13 potentiated the analgesic effect induced by morphine (i.c.v., 5 microg/kg) and this potentiated effect can be also reversed by naloxone.

Topics: Analgesia; Analgesics, Opioid; Animals; Apelin Receptors; Injections, Intraventricular; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred Strains; Morphine; Narcotic Antagonists; Pain; Receptors, G-Protein-Coupled; Receptors, Opioid; Time Factors