Spinal antinociceptive effects of the novel NOP receptor agonist PWT2‐nociceptin/orphanin FQ in mice and monkeys

Abstract

Background and purposeUsing an innovative chemical approach, peptide welding technology (PWT), a tetrabranched derivative of nociceptin/orphanin FQ (N/OFQ) has been generated and pharmacologically characterized. Both in vitro and in vivo PWT2‐N/OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer‐lasting effects. The aim of the present study was to investigate the spinal effects of PWT2‐N/OFQ in nociceptive and neuropathic pain models in mice and non‐human primates.Experimental ApproachTail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N/OFQ and PWT2‐N/OFQ were assessed in these models.Key ResultsPWT2‐N/OFQ mimicked the spinal antinociceptive effects of N/OFQ both in nociceptive and neuropathic pain models in mice as well as in non‐human primates displaying 40‐fold higher potency and a markedly prolonged duration of action. The effects of N/OFQ and PWT2‐N/OFQ were sensitive to the N/OFQ receptor (NOP) antagonist SB‐612111, but not to opioid receptor antagonists.Conclusions and ImplicationsThe present study has demonstrated that PWT2‐N/OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non‐human primates acting as a potent and longer‐lasting NOP‐selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.

Central N/OFQ-NOP Receptor System in Pain Modulation

“…More importantly, this largely increased potency and improved duration of action exhibited by PWT2-N/OFQ can be translated from rodents to primates. Intrathecal administration of PWT2-N/OFQ potently produced full antinociceptive effects lasted for more than 24 hours in monkeys (Rizzi et al, 2015). Under similar experimental conditions, PWT2-N/OFQ (0.3–3 nmol) is approximately 30-fold more potent than N/OFQ (10–100 nmol) and the duration of antinociceptive action of PWT2-N/OFQ (~24 hours) is 10-fold longer than that of N/OFQ (~2.5 hours) in primates (Ding et al, 2015b; Ko et al, 2006; Rizzi et al, 2015).…”

“…Intrathecal administration of PWT2-N/OFQ potently produced full antinociceptive effects lasted for more than 24 hours in monkeys (Rizzi et al, 2015). Under similar experimental conditions, PWT2-N/OFQ (0.3–3 nmol) is approximately 30-fold more potent than N/OFQ (10–100 nmol) and the duration of antinociceptive action of PWT2-N/OFQ (~24 hours) is 10-fold longer than that of N/OFQ (~2.5 hours) in primates (Ding et al, 2015b; Ko et al, 2006; Rizzi et al, 2015). It is worth noting that among all agonists selective for opioid receptor subtypes, NOP receptor agonists are the only class of drugs that are able to change the nociceptive threshold of primates without side effects commonly caused by MOP receptor agonists (Lin & Ko, 2013).…”

Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13)

“…The PWT has been applied to different peptide sequences including nociceptin/orphanin FQ (N/OFQ) (Rizzi et al, 2014; Rizzi et al, 2015), neuropeptide S (Ruzza et al, 2015), and tachykinins (substance P, neurokinin A and B) (Ruzza et al, 2014). These studies demonstrated that PWT derivatives maintained the in vitro pharmacological profile (pharmacological activity, potency and selectivity of action) of the parent peptide sequences while showing higher in vivo potency and particularly long lasting action.…”

Nociceptin/orphanin FQ receptor and pain: Feasibility of the fourth opioid family member

“…route ultralow doses of N/OFQ (fmol) produced spontaneous agitation and painlike behavior in mice (Sakurada et al, 1999), whereas at nanomolar dose range produced antinociceptive effects clearly demonstrated by several laboratories (Lin and Ko, 2012;Micheli et al, 2015a;Rizzi et al, 2015). Recently, we compared the spinal antinociceptive properties of N/OFQ and two NOP peptide agonists developed by the University of Ferrara, UFP-112 and UFP-113 (full and partial NOP agonist, respectively; Arduin et al, 2007;Rizzi et al, 2007;Calò et al, 2011) antinociceptive action comparable to 1-3 nmol/h morphine or N/OFQ.…”