Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/μ-opioid receptor ligands in mouse models of neuropathic and inflammatory pain

Abstract

Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics.

Fig. 1.

Antiallodynic effects of intrathecal administration of SCH221510 and morphine in mice with neuropathic pain. Effects of SCH221510 (A) and morphine (C) on paw withdrawal thresholds (g). Percentage of maximum possible effect of SCH221510 (B) and morphine (D) for attenuating tactile allodynia. BL, baseline values before induction of nerve injury. Pre-, predrug values before intrathecal administration of drugs. Behavioral responses were measured at 0.5, 1, 2, 3, 4, 24, and 48 hours after drug administration. Each value represents the mean ± S.E.M. (n = 6). Symbols represent different dosing conditions in different groups of mice. *Statistically significant difference from the vehicle controls (○, 0 µg) (P < 0.05).

Fig. 2.

Antihyperalgesic effects of intrathecal administration of SCH221510 and morphine in mice with inflammatory pain. Effects of SCH221510 (A) and morphine (C) on paw withdrawal latencies (sec). Percentage of maximum possible effect of SCH221510 (B) and morphine (D) for attenuating thermal hyperalgesia. BL, baseline values before induction of paw inflammation. Pre-, predrug values before intrathecal administration of drugs. Behavioral responses were measured at 0.5, 1, 2, 3, 4, 24, and 48 hours after drug administration. Each value represents the mean ± S.E.M. (n = 6). Symbols represent different dosing conditions in different groups of mice. *Statistically significant difference from the vehicle controls (○, 0 μg) (P < 0.05).

Fig. 3.

Antiallodynic effects of intrathecal administration of BU08028, SR16435, and buprenorphine in mice with neuropathic pain. Effects of BU08028 (A), SR16435 (C), and buprenorphine (E) on paw withdrawal thresholds (g). Percentage of maximum possible effect of BU08028 (B), SR16435 (D), and buprenorphine (F) for attenuating tactile allodynia. BL, baseline values before induction of nerve injury. Pre-, predrug values before intrathecal administration of drugs. Behavioral responses were measured at 0.5, 1, 2, 3, 4, 24, and 48 hours after drug administration. Each value represents the mean ± S.E.M. (n = 8). Symbols represent different dosing conditions in different groups of mice. *Statistically significant difference from the vehicle controls (○, 0 μg) (P < 0.05).

Fig. 4.

Antihyperalgesic effects of intrathecal administration of BU08028, SR16435, and buprenorphine in mice with inflammatory pain. Effects of BU08028 (A), SR16435 (C), and buprenorphine (E) on paw withdrawal latencies (sec). The % maximum possible effect of BU08028 (B), SR16435 (D), and buprenorphine (F) for attenuating thermal hyperalgesia. BL, baseline values before induction of paw inflammation. Pre-, predrug values before intrathecal administration of drugs. Behavioral responses were measured at 0.5, 1, 2, 3, 4, 24, and 48 hours after drug administration. Each value represents the mean ± S.E.M. (n = 8). Symbols represent different dosing conditions in different groups of mice. *Statistically significant difference from the vehicle controls (○, 0 μg) (P < 0.05).

Fig. 5.

Comparison of the antinociceptive potencies of intrathecally administered NOP- and MOP-related ligands in neuropathic and inflammatory pain at 0.5 hours after drug administration. Dose-response curves for of BU08028, SR16435, buprenorphine, morphine, and SCH221510 for their antiallodynic effects against neuropathic pain (A) and antihyperalgesic effects against inflammatory pain (B). Different symbols represent different drugs. (C) Comparison of the antinociceptive effects as ED₅₀ + 95% confidence interval values of BU08028, SR16435, buprenorphine, morphine, and SCH221510: ○ represents each drug’s ED₅₀ against neuropathic pain, and □ represents each drug’s ED₅₀ against inflammatory pain.

Fig. 6.

Effects of NOP and MOP antagonists on antiallodynic effects of intrathecal SCH221510 (10 µg) and morphine (10 µg) in neuropathic pain. Antagonists were administered intrathecally 10 minutes before SCH221510 or morphine. Changes in SCH221510-induced increase in the paw withdrawal thresholds (A) and the percentage of maximum possible antiallodynic effect (B) after J-113397, naltrexone, or vehicle pretreatment at 0.5 hours after intrathecal SCH221510. Right panels: changes in morphine-induced increase in the paw withdrawal thresholds (B) and the percentage of maximum possible antiallodynic effect (D) after naltrexone, J-113397, or vehicle pretreatment at 0.5 hours after intrathecal morphine. *Statistically significant difference from the vehicle control (P < 0.05).

Fig. 7.

Effects of NOP and MOP antagonists on antiallodynic effects of intrathecal BU08028 (1 µg), SR16435 (3 µg) and buprenorphine (3 µg) in neuropathic pain at 0.5 hours. Antagonists J-113397 (3 µg), naltrexone (3 µg), or combination of naltrexone and J-113397 (3 µg) were intrathecally administered as a 10-minute pretreatment. Top panels: effects of antagonists on increased paw withdrawal thresholds (g) induced by BU08028 (A), SR16435 (C), and buprenorphine (E). Bottom panels: effects of antagonists on percentage of maximum possible antiallodynic effects of BU08028 (B), SR16435 (D), and buprenorphine (F). *Statistically significant difference from the vehicle control (P < 0.05).

Fig. 8.

Development of tolerance to the antiallodynic effects of repeated intrathecal administration of SR16435 (3 µg) or buprenorphine (3 µg) in mice with neuropathic pain. (A) Changes in SR16435 and buprenorphine-induced increase in paw withdrawal thresholds (g). (B) Changes in SR16435- and buprenorphine-induced percentage of maximum possible antiallodynic effects. Mice were tested each day at 0.5 hours after the drug administration. ▪ is SR16435; ● is buprenorphine. #Statistically significant difference from the antiallodynic effects of SR16435 on day 1 of the treatment. *Statistically difference from the antiallodynic effects of buprenorphine on day 1 (P < 0.05).