Neuropeptide FF Receptors Have Opposing Modulatory Effects on Nociception

Abstract

The role of neuropeptide FF (NPFF) and its analogs in pain modulation is ambiguous. Although NPFF was first characterized as an antiopioid peptide, both antinociceptive and pronociceptive effects have been reported, depending on the route of administration. Currently, two NPFF receptors, termed FF1 and FF2, have been identified and cloned, but their roles in pain modulation remain elusive because of the lack of availability of selective compounds suitable for systemic administration in in vivo models. Ligand-binding studies confirm ubiquitous expression of both subtypes in brain, whereas only FF2 receptors are expressed spinally. This disparity in localization has served as the foundation of the hypothesis that FF1 receptors mediate the pronociceptive actions of NPFF. We have identified novel small molecule NPFF receptor agonists and antagonists with varying degrees of FF2/FF1 functional selectivity. Using these pharmacological tools in vivo has allowed us to define the roles of NPFF receptor subtypes as pertains to the modulation of nociception. We demonstrate that selective FF2 agonism does not modulate acute pain but instead ameliorates inflammatory and neuropathic pains. Treatment with a nonselective FF1/FF2 agonist potentiates allodynia in neuropathic rats and increases sensitivity to noxious thermal and to non-noxious mechanical stimuli in normal rats in an FF1 antagonist-reversible manner. Treatment with FF1 antagonists reversed established mechanical allodynia, indicating the possibility of increased NPFF tone through FF1 receptors. In conclusion, we provide evidence for the opposing roles of NPFF receptors and highlight selective FF2 agonism and/or selective FF1 antagonism as potential targets warranting further investigation.

Kisspeptin modulates the activity of the stress system and associated behaviours, the body temperature and nociception

“…Additionally, receptor binding data and two different functional assays provide further support, in which all RF-amide peptides were found to target NPFF1R and NPFF2R in a nanomolar concentration range [50]. Furthermore, both NPFF1R and NPFF2R have been previously indicated in the modulation of pain [102]. Hence, these results indicate NPFFR involvement, at least, in the central kisspeptin actions rather then KISS1R mediation.…”

“…administration of NPFF induce hyperalgesia and/or inhibit opioid-induced analgesia [58], whereas intrathecal injection results in the opposite [165]. Both in vitro and in vivo pharmacological data suggest that these effects are mediated by the activation of NPFF1R and NPFF2R receptors [102], respectively. Distribution data indicate that NPFF2R is found most abundantly in the spinal cord, whereas in the brain both receptors are highly expressed, especially NPFF1R [16,114,231].…”

“…NPFF and analogues were found to have analgesic, pronociceptive and morphine modulating activities [56]. Although initially described as a solely antiopioid system, evidence proved otherwise and now it is believed that the nature of the pharmacology depends on the subtype targeted, route of administration, and opioid activity [102]. In point of fact, icv.…”

“…Several studies show, for example, that RF-amide peptides play a prominent role in nociception: intracerebroventricular (icv.) administration cause hyperalgesia and inhibition of morphine-induced analgesia, which effect is shared by all RF-amide peptides [102,50]. Furthermore, PrRP activates the hypothalamic-pituitary-adrenal (HPA) axis [129] and increases stereotyped locomotion [105] and pressor response [76].…”

“…NPFF and analogues were found to have analgesic, pronociceptive and antinociceptive, and furthermore morphine modulating activities. Evidence suggests that these effects are mediated by the activation of NPFF1R and NPFF2R receptors, respectively [102,165]. Additionally, all endogenous RFamide peptides seem to target not only their cognate receptors, but the NPFF1R and NPFF2R receptors as well, which argue for their role in pain modulation [50].…”