Effects Of Neuropreptide FF On Peripheral Analgesia Of Opioids And The Spinal Cardiovascular System

Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family, including two precursors (pro-NPFFA and pro-NPFFB) and two receptors (NPFF1 and NPFF2). NPFF has been reported to play important roles in the control of pain, cardiovascular activity, opiate tolerance and addiction, body temperature and gastrointestinal function through interactions with the opioid system. In order to further explore the biological function of NPFF system, in the present study, NPFF and its selective ligands were used to investigate the regulatory effects of NPFF system on peripheral analgesia induced by opioids and the spinal cardiovascular activities.In the mouse tail flick test, the effects of central administration of NPFF and related peptides on analgesia induced by morphine administered at the peripheral level were studied. The result showed that intracerebroventricular (i.c.v.) injection of NPFF (1,3 and 10 nmol) dose-dependently inhibited the analgesia induced by morphine (0.12 mg, i.p.) administered at the peripheral level. Similarly, i.c.v. administration of dNPA and NPVF, two agonists highly selective for NPFF2 and NPFF1 receptors, respectively, decreased the peripheral antinociceptive effect of 0.12 mg morphine in mice. Furthermore, these anti-opioid activities of NPFF and related peptides were blocked by pretreatment with the NPFF receptors selective antagonist RF9 (10 nmol, i.c.v.). These results demonstrate that activation of central NPFF1 and NPFF2 receptors has the similar anti-opioid action on the peripheral analgesic effect of morphine.In urethane-anesthetized rats, the cardiovascular responses to intrathecal (i.t.) injection of NPFF and related agonists were investigated. It is noteworthy that NPFF elicited increases in mean arterial pressure (MAP) and heart rate (HR) in a dose-dependent manner. Interestingly, NPVF and dNPA, the two highest selective agonists for NPFF1 and NPFF2 receptors, produced significant pressor and tachycardic responses at the spinal cord level. Furthermore, the cardiovascular effects induced by NPFF and related peptides were significantly antagonized by NPFF receptors selective antagonist RF9 (i.t.). Moreover, pretreatment of the rats with a-adrenoceptor antagonist phentolamine (1 mg/kg, i.v.) significantly reduced the pressor effects of NPFF. Nevertheless, pretreatment with muscarinic receptor and adrenoceptor antagonists (i.v.) could block the tachycardic effects induced by NPFF. Collectively, our results suggested that i.t. administration of NPFF and related peptides increased MAP and HR which were possibly mediated by the activation of both NPFF1 and NPFF2 receptors in the rat spinal cord. In addition, our results showed that the muscarinic receptor and adrenoceptor participated in the tachycardic response to i.t. NPFF, whileα-adrenoceptor played an important role in the regulation of pressor effect of NPFF (i.t.).