Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain

Abstract

Nociceptin/orphanin FQ (noci/OFQ), the endogenous ligand for the orphan ORL1 (opioid receptor-like1), has been shown to be anti- or pronociceptive and modify morphine analgesia in rats after central administration. We comparatively examined the effect of noci/OFQ on hyperalgesia and morphine analgesia in two experimental models of neuropathic pain: diabetic (D) and mononeuropathic (MN) rats. Noci/OFQ, when intrathecally (i.t.) injected (0.1, 0.3, or 1, to 10 microg/rat) was ineffective in normal rats, but reduced and suppressed mechanical hyperalgesia (paw-pressure test) in D and MN rats, respectively. This spinal inhibitory effect was suppressed by naloxone (10 microg/rat, i.t.) in both models. Combinations of systemic morphine with spinal noci/OFQ resulted in a strong potentiation of analgesia in D rats. In MN rats, an isobolographic analysis showed that the morphine+noci/OFQ association (i.t.) suppressed mechanical hyperalgesia in a superadditive manner. In summary, the present findings reveal that spinal noci/OFQ produces a differential antinociception in diabetic and traumatic neuropathic pain according to the etiology of neuropathy, an effect possibly mediated by opioid receptors. Moreover, noci/OFQ combined with morphine produces antinociceptive synergy in experimental neuropathy, opening new opportunities in the treatment of neuropathic pain.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Although morphine is considered selective for m-opioid receptors, selective agonists of the other three members of the extended opioid receptor family (i.e., d-and k-opioid receptors, and nociceptin receptors) also functionally inhibit Ca V 2.2 channels (Gross and Macdonald, 1987;Moises et al, 1994;Motin et al, 1995;Morikawa et al, 1998;Toselli et al, 1999;Larsson et al, 2000;Yeon et al, 2004;Ruiz-Velasco et al, 2005;Evans et al, 2010). As in the case of m-opioid receptors, their activation induces analgesia in various animal models of pain (King et al, 1997;Darland et al, 1998;Field et al, 1999;Mika et al, 2001;Courteix et al, 2004;Nozaki et al, 2012). Although there are no clinically approved d-opioid-and nociceptin receptor-targeting analgesics, there is at least one k-opioid receptor agonist (pentazocine) that is used in humans as an analgesic.…”

Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia

“…Many of its activities, including its antiopiate action, appear to be region and assay specific. Although antiopioid when injected i.c.v., N/OFQ can be analgesic in the spinal cord (46,47) and an effective analgesic when injected intrathecally in chronic-pain models (48). The relative activities of N/OFQ agonists and antagonists in chronic-pain models are not clear since both N/OFQ and the potent and selective NOP antagonist SB-612111 have been reported to show antihyperalgesic activity (48,49).…”

Antihyperalgesic Effect of Buprenorphine Involves Nociceptin/Orphanin FQ Peptide–Receptor Activation in Rats With Spinal Nerve Injury–Induced Neuropathy

“…Chemicals in a volume of 10 L were injected through the catheter, followed by flushing with 10 L of saline. (12,13). Naloxone was administered i.p.…”

“…Actually, our study demonstrates that the antihyperalgesic effect of buprenorphine at the lower doses involves activation of both NOP receptors and opioid receptors in neuropathic rats, while the analgesic effect of buprenorphine at the higher doses is mediated predominantly by opioid receptor activation, but independent of NOP receptors, in naïve rats. Synergistic analgesia caused by coactivation of NOP receptors and -opioid receptors has been reported in primates (4) and rodents (12). Interestingly, NOP receptors in the dorsal root ganglia (DRG) are upregulated in rats with neuropathy induced by partial sciatic nerve transection (14).…”

“…Interestingly, NOP receptors in the dorsal root ganglia (DRG) are upregulated in rats with neuropathy induced by partial sciatic nerve transection (14). It has also been reported that intrathecal administration of NOP at 0.1 -10 g/rat had no effect on nociception in naïve rats, but suppressed neuropathic hyperalgesia in diabetic rats and in rats with mild chronic constrictive injury of the sciatic nerve (12). These reports support the present evidence that both NOP receptors and -opioid receptors contribute to the antihyperalgesic activity of buprenorphine in neuropathic rats.…”