sr140333b and Pain

The present study focused on the interactive effects of (Mpa(6))-γ2-MSH-6-12 (Mpa, spinal level) and endokinin A/B (EKA/B, supraspinal level) on pain regulation in mice. EKA/B (30 pmol) only weakened 100 pmol Mpa-induced hyperalgesia at 5 min, but could enhance it during 20-30 min. However, EKA/B (100 pmol) antagonized all dose levels of Mpa significantly at 5 min and blocked them completely at 10 min. EKA/B (3 nmol) co-injected with Mpa presented marked analgesia at 5 min and enduring hyperalgesia within 20-60 min. To investigate the underlying mechanisms between Mpa and EKA/B, SR140333B and SR142801 (NK1 and NK3 receptor antagonists, respectively) were utilized. SR140333B had no influence on Mpa, while SR142801 potentiated it during 20-30 min. Whereas, SR140333B and SR142801 could block the co-administration of Mpa and EKA/B (30 pmol) separately at 5 min and 30 min. These phenomena might attribute to that these two antagonists promoted the antagonism of EKA/B (30 pmol) at the early stage, while antagonized EKA/B preferentially in the latter period. SR140333B weakened the analgesia of EKA/B (3 nmol), but produced no effect on Mpa. However, SR140333B failed to affect the co-injection of Mpa and EKA/B, which implied that EKA/B cooperated with Mpa prior to SR140333B. These results could potentially help to better understand the interaction of NK and MrgC receptors in pain regulation in mice.

Topics: Animals; Dose-Response Relationship, Drug; gamma-MSH; Hyperalgesia; Injections, Intraventricular; Injections, Spinal; Male; Mice; Neurokinin A; Neurokinin B; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Piperidines; Receptors, Neurokinin-3; Tropanes

Endokinins are novel tachykinins encoded on the human TAC4 and consist of Endokinin A (EKA), B (EKB), C (EKC) and D (EKD). To date, the function of Endokinins in pain processing was not fully understood. Therefore the aim of this study was to investigate the effects of Endokinin A/B (EKA/B, the common C-terminal decapeptide in EKA and EKB) and Endokinin C/D (EKC/D, the common C-terminal duodecapeptide in EKC and EKD) on pain modulation at supraspinal level in mice. Intracerebroventricular (i.c.v.) administration of EKA/B (1, 3, 12, 20nmol/mouse) dose dependently induced potent analgesic effect. This effect could be fully antagonized by SR140333B but not SR48968C or SR142801. Naloxone could also block the analgesic effect, suggesting that this analgesic effect is related to opioid receptors. However, i.c.v. administration of EKA/B (10, 30, 100pmol/mouse) caused hyperalgesic effect significantly, with a "U" shape curve. Interestingly, the hyperalgesic effect induced by EKA/B could be attenuated by SR140333B, SR142801 but not SR48968C. I.c.v. administration of EKC/D (1, 3, 12, 20nmol/mouse) also dose dependently induced analgesic effect, which could not be blocked by SR48968C or SR142801 or naloxone. But to our astonishment, it could be significantly enhanced by SR140333B. More interestingly, the hyperalgesic effect induced by EKA/B could be significantly attenuated by EKC/D. In addition, the analgesic effect induced by co-administration of EKA/B and EKC/D was much less stronger than the effect of either EKA/B or EKC/D.

Topics: Analgesics; Animals; Antipsychotic Agents; Benzamides; Humans; Hyperalgesia; Injections, Intraventricular; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peptide Fragments; Piperidines; Receptors, Tachykinin; Tachykinins; Tropanes

In our previous study, Endokinin A/B (EKA/B, the common C-terminal decapeptide in Endokinin A and Endokinin B) was found to induce analgesic effect at high dose and nociception at low dose, while Endokinin C/D (EKC/D, the common C-terminal duodecapeptide in Endokinin C and Endokinin D) has analgesic effect only. So in this study an attempt was undertaken to investigate the interaction of EKA/B and EKC/D with Endomorphin-1 (EM-1) on antinociceptive effect at supraspinal level. Results showed that the antinociceptive effect of EM-1 was enhanced by high dose of EKA/B and abolished by low dose of EKA/B, while EKC/D could only enhance the analgesic effect. Mechanism studies showed that EKA/B blocked the antinociception of EM-1 by activating neurokinin-1 receptor (NK(1)), whose specific antagonist, SR140333B could fully block EKA/B-induced attenuation on the analgesic response of EM-1. Surprisingly, EKC/D could also block the same EKA/B-induced attenuation. Taken together, the different effects of EKA/B and EKC/D on the antinociception of EM-1 may pave the way for a new strategy on investigating the interaction between tachykinins and opioids on pain modulation.

Topics: Analgesics, Opioid; Animals; Humans; Male; Mice; Naloxone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Oligopeptides; Pain; Pain Measurement; Protein Isoforms; Protein Precursors; Tachykinins; Tropanes

Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian tachykinin peptides encoded by the recently identified TAC4 gene in human, and the biological functions of these peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in pain modulation at the supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of h HK-1 (0.3, 1, 3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the NK(1) receptor antagonist SR140333, but not by the NK(2) receptor antagonist SR48968, indicating that the analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of NK(1) receptors. Interestingly, naloxone, beta-funaltrexamine and naloxonazine, but not naltrindole and nor-binaltorphimine, could also block the analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent analgesic effect after i.c.v. administration, however, the potency of analgesia was less than h HK-1. Surprisingly, SR140333 could not modify this analgesic effect, suggesting that this effect is not mediated through the NK(1) receptors like h HK-1. SR48968 could modestly enhance the analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to NK(2) receptors. Furthermore, none of the opioid receptor (OR) antagonists could markedly block the analgesia of h HK-1(4-11), suggesting that the analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta ORs significantly enhanced the analgesia, indicating that delta OR is a negatively modulatory factor in the analgesic effect of h HK-1(4-11). It is striking that bicuculline (a competitive antagonist at GABA(A) receptors) effectively blocked the analgesia induced by h HK-1(4-11), suggesting that this analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of pain.

Topics: Analgesics; Animals; Benzamides; Bicuculline; Dose-Response Relationship, Drug; GABA Antagonists; Humans; Injections, Intraventricular; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Peptide Fragments; Piperidines; Receptors, Neurokinin-2; Tachykinins; Tropanes