Differential effects of nociceptin/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP/μ receptor agonists in the sciatic nerve ligation chronic pain model in mice

Abstract

1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and μ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery, SR14150 but not SR16835 increased tail-flick latency, which was blocked by the opioid antagonist naloxone, but not by the NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). In contrast, both SR14150 and SR16835 had antiallodynic activity when mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by SB-612111 but not by naloxone. On the other hand, morphine antinociception and antiallodynia were both blocked by naloxone and potentiated by SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and chronic pain states is different. It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.

Fig. 1.

Chemical structures of SR14150 and SR16835.

Fig. 2.

Effect of SR14150 administered alone (A) or coadministered with NOP receptor antagonist SB-612111 or opioid antagonist naloxone (B) on tail-flick latency in mice that have undergone SNL. Morphine is included as the positive control. Data are means ± S.E.M. *, significant difference from vehicle controls; +, significant difference from morphine control; †, significant difference from SR14150 alone (P < 0.05).

Fig. 3.

Effect of SR14150 administered alone (A) or coadministered with NOP receptor antagonist SB-612111 or opioid antagonist naloxone (B) on mechanical allodynia induced by SNL. Morphine is included as the positive control. Data are means ± S.E.M. *, significant difference from vehicle controls; †, significant difference from SR14150 alone (P < 0.05).

Fig. 4.

Effect of SR16835 administered alone on tail-flick latency in mice that have undergone SNL. Morphine is included as the positive control. Data are means ± S.E.M. *, significant difference from vehicle controls (P < 0.05).

Fig. 5.

Effect of SR16835 administered alone (A) or coadministered with NOP receptor antagonist SB-612111 or opioid antagonist naloxone (B) on mechanical allodynia induced by SNL. Morphine is included as the positive control. Data are means ± S.E.M. *, significant difference from vehicle controls; +, significant difference from morphine control; †, significant difference from SR16835 alone (P < 0.05).

Fig. 6.

Effect of morphine administered alone or coadministered with NOP receptor antagonist SB-612111 or opioid antagonist naloxone on tail-flick latency in mice that have undergone SNL. Data are means ± S.E.M. *, significant difference from vehicle controls; +, significant difference from morphine alone (P < 0.05).

Fig. 7.

Effect of morphine administered alone (A) or coadministered with NOP receptor antagonist SB-612111 or opioid antagonist naloxone (B) on mechanical allodynia induced by SNL. Data are means ± S.E.M. *, significant difference from vehicle controls; +, significant difference from morphine alone (P < 0.05).