Reversal of morphine tolerance by a compound with NPFF receptor subtype-selective actions

Abstract

Neuropeptide FF (NPFF) modulates opiate actions. It has pro-nociceptive effects, primarily through the NPFF receptor 1 subtype, and anti-nociceptive effects, primarily through the NPFFR2 subtype. AC-263093 is a small l, organic, systemically active molecule that was previously shown to functionally activate NPFFR2, but not NPFFR1. It was hypothesized that AC-263093 would attenuate morphine tolerance. Rats were tested for radiant heat tail-flick latency before and after 5 mg/kg morphine sulfate s.c. They were then rendered morphine-tolerant by continuous subcutaneous infusion of 17.52 mg/kg/day morphine sulfate. On the seventh day of infusion, they were retested for analgesia 10 and 20 min after 5mg/kg morphine sulfate s.c. Tolerance was indicated by reduction of morphine analgesia from the pre-infusion test. Fifty minutes prior to morphine challenge, rats received either 10 mg/kg i.p. AC-263093 or injection vehicle alone. AC-2623093-treated rats had far smaller tolerance scores than control rats. This drug effect was significant, p = 0.015. The same dose of AC-263093 had almost no analgesic effect in non-tolerant, saline-infused rats. In vitro experiments revealed that AC-263093 had equal affinity for NPFFR1 and NPFFR2, and functionally inactivated NPFFR1, in addition to its previously shown ability to activate NPFFR2. Thus, altering the balance between activation of NPFF receptor subtypes may provide one approach to reversing opiate tolerance.

Altered nociception and morphine tolerance in neuropeptide FF receptor type 2 over‐expressing mice

“…NPFFR1 activation might hypothetically oppose the effects of NPFFR2, dominate NPFF system activity during chronic morphine treatment, and contribute to the development of tolerance to morphine antinociception. This hypothesis could be supported by a recent study (Malin et al., ) that reported AC263093 could reverse morphine tolerance and processes equal binding affinity towards NPFFR1 and NPFFR2 (pKi of 7.0 vs. 6.9, respectively). Interestingly, authors demonstrated AC263093 acts as an NPFFR1 antagonist but NPFFR2 agonist and argued the attenuation of morphine tolerance could be due to either NPFFR1 antagonism or NPFFR2 stimulation (Malin et al., ).…”

“…This hypothesis could be supported by a recent study (Malin et al., ) that reported AC263093 could reverse morphine tolerance and processes equal binding affinity towards NPFFR1 and NPFFR2 (pKi of 7.0 vs. 6.9, respectively). Interestingly, authors demonstrated AC263093 acts as an NPFFR1 antagonist but NPFFR2 agonist and argued the attenuation of morphine tolerance could be due to either NPFFR1 antagonism or NPFFR2 stimulation (Malin et al., ). Nevertheless, the mechanisms underlying NPFFR2‐mediated attenuation of morphine tolerance remains unknown.…”

Central and peripheral modulation of gastrointestinal transit in mice by DN‐9, a multifunctional opioid/NPFF receptor agonist

“…18 Numerous reports suggest that NPFF exerts antiopioid activities and antagonizes opioid-induced actions including analgesia, tolerance, and reward. [42][43][44] In the present study, we explored the roles of the NPFF agonism in DN-9-induced GI inhibition. Previous studies have demonstrated that NPFF and FMRFamide cause significant contractions in the isolated mouse distal colon and porcine GI smooth muscle.…”

BN‐9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance‐forming antinociception in mice

“…These findings imply the important role of the activation of NPFF receptors in delaying opioid tolerance development to BN‐9. Indeed, previous studies have shown that both an antagonist (RF9) and agonist (AC‐263093) of NPFF receptors decrease morphine tolerance to antinociception (Simonin et al , ; Elhabazi et al , ; Malin et al , ). These conflicting results highlight the complicated relationship between NPFF receptor activation and opioid‐mediated tolerance.…”