Regular paperFunctional studies using antibodies against orphanin FQ/nociceptin
Introduction
It has been suggested that Orphanin FQ/nociceptin (OFQ) represents the fourth endogenous opioid peptide and joins the ranks of the well-described enkephalins, endorphins, and dynorphins. The description of the chemical structure of OFQ was immediately followed by a flurry of biochemical and physiological studies. One of the most interesting questions was whether OFQ possessed analgesic properties similar to other opioid peptides.
The actions of OFQ on pain modulation have been shown to depend on the site of administration, and consensus opinion is that OFQ exhibits pronociceptive actions in the brain (hence the name nociceptin) and antinociceptive actions in the spinal cord [4], [8], [9], [10], [12], [13], [14], [15], [19]. These data were obtained using conventional pharmacological methodology where exogenous peptide was administered directly into the central nervous system (CNS). Using this paradigm, it is not possible to differentiate the physiological from pharmacological effects of the applied peptide.
More rational approaches for the study of an endogenously released neuropeptide are based around examining the effects of a functional deficit. This functional deficit can be produced by blockade of peptide biosynthesis, neutralization of the released peptide, and/or occupation of its specific receptor.
The current understanding of the metabolic processing of neuropepetides is far less clear than those for classic neurotransmitters; it is therefore premature to design a specific inhibitor targeting the enzymatic processing of an identified peptide. While the opioid receptor-like receptor 1 (ORL1)/LC132 has been demonstrated to be the specific receptor for OFQ, there is still a relative paucity of specific antagonists for this system. In 1998, Guerrini et al. [6] reported that [Phe1 89 (CH2-NH) Gly2]NC(1–13)]NH2 acted as a specific antagonist for OFQ receptor found in a range of peripheral tissues. However, due to the variable agonist and antagonist activity of this peptide in a range of preparations, its usefulness is questionable [1], [2], [3], [5], [17], [18].
Section snippets
Rationale and methodological considerations for the use of OFQ antibodies
The administration of specific antibodies against OFQ to discrete brain sites, thereby neutralizing endogenous peptide released from nerve terminals, represents an additional approach to study the physiological function of OFQ. More specifically using antibody microinjection techniques, it is possible to produce selective OFQ inactivation. This approach will provide a unique opportunity to differentiate OFQ from other closely related peptides and represents a major advantage of antibody
Effects of OFQ antibody on morphine and EA analgesia
Our earlier work indicated that i.c.v. OFQ antagonized morphine and electroacupuncture (EA) analgesia, while i.t. OFQ increased morphine and EA analgesia [14], [15]. These bidirectional modulatory actions of OFQ on morphine and EA analgesia have since been supported by others [4], [8], [9], [10], [12], [13], [19].
We have further studied this bidirectional modulation by injecting an OFQ antibody into the cerebral ventricle and spinal subarachnoid space. Specifically, we asked the question, could
Effects of OFQ antibody on morphine and EA tolerance
Considering the potent anti-opioid actions of OFQ in the brain, one can expect that brain OFQ may also play a role in the development of tolerance to morphine and EA analgesia. We have studied this further. Chronic morphine tolerance was produced in rats by repeated injection of morphine (5–60 mg/kg, s.c., three times a day) for 6 days. In these animals, i.c.v. injection of OFQ-Ab (1:1 dilution) reversed chronic morphine tolerance by 50% (P < 0.01) (Fig. 3). Chronic tolerance to the analgesic
Concluding statement
Collectively, data obtained by central administration of OFQ or OFQ antibodies suggest that endogenously released OFQ plays an important role in pain modulation, i.e. increased pain sensitivity in the brain and lowered pain sensitivity in the spinal cord.
References (20)
- et al.
[Phe1psi(CH2-NH)Gly2] nociceptin-(1–13)-NH2 is an agonist of the nociceptin (ORL1) receptor
Eur J Pharmacol
(1998) - et al.
[Phe1psi(CH2-NH)Gly2]nociceptin-(1–13)-NH2 acts as an agonist of the orphanin FQ/nociceptin receptor in vivo
Eur J Pharmacol
(1998) - et al.
Met-enkephalin-Arg6-Phe7-like immunoreactive substances mediate electroacupuncture analgesia in the periaqueductal gray of the reabbit
Brain Res
(1984) - et al.
Spinal analgesic activity of orphanin FQ/nociceptin and its fragments
Neurosci Lett
(1997) - et al.
Orphanin FQ is a functional anti-opioid peptide
Neuroscience
(1996) - et al.
Orphanin FQ is the major OFQ 1–17-containing peptide produced in the rodent and monkey hypothalamus
Peptide
(1998) - et al.
Naloxone sensitive orphanin FQ-induced analgesia in mice
Eur J Pharmacol
(1996) - et al.
Supraspinal hyperalgesia and spinal analgesia by [Phe1psi(CH2-NH)Gly2]nociceptin-(1–13)-NH2 in rat
Eur J Pharmacol
(1999) - et al.
[Phe1psi(CH2-NH)Gly2]nociceptin-(1–13)-NH2, a proposed antagonist of the nociceptin receptor, is a potent and stable agonist in the rat spinal cord
Neurosci Lett
(1998) - et al.
Accelerated release and production of orphanin FQ in brain of chronic morphine tolerant rats
Brain Res
(1999)
Cited by (28)
Dose-effect relationship between electroacupuncture with different parameters and the regulation of endogenous opioid peptide system
2024, World Journal of Acupuncture - MoxibustionNociceptin/orphanin FQ receptor and pain: Feasibility of the fourth opioid family member
2015, European Journal of PharmacologyCitation Excerpt :Noteworthy, N/OFQ administered intracerebroventricularly (i.c.v.) in rodents was pronociceptive and inhibited morphine antinociception (Calò et al., 1998; Tariq et al., 2013). Further studies using i.c.v. injection of N/OFQ antisera showed attenuated development of tolerance to morphine (Tian and Han, 2000). In rodents, the anti-opioid actions of N/OFQ seems related to an interaction with the descending inhibitory control machinery from the rostral ventromedial medulla (RVM) back to the spinal dorsal horn.
Deciphering intracellular localization and physiological role of nociceptin and nocistatin
2013, PeptidesCitation Excerpt :Many studies have indicated the opioid-modulating role for N/OFQ; however, activation of the endogenous N/OFQ system after opioid receptor stimulation has been hardly demonstrated. Further studies using central injection of N/OFQ antisera showed attenuated development of tolerance to morphine- and electroacupuncture-induced analgesia [159]. N/OFQ administered supraspinally reverses the effects of exogenous opioids.
Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment
2012, NeuropharmacologyCitation Excerpt :Therefore, it seems that morphine dose, species and method of pain measurement account for the discrepancy. Several lines of evidence suggest endogenous N/OFQ plays an important role in the development of morphine tolerance (Tian and Han, 2000; Yuan et al., 1999; Ueda et al., 2000, 2001; Zaratin et al., 2004; Chung et al., 2006) therefore we analyzed levels of N/OFQ by RIA in spinal cord, CSF and PAG samples. Spinal N/OFQ levels were higher in opioid naïve and chronic morphine-treated female rats than male rats (Fig. 2A).
The role of nociceptin and dynorphin in chronic pain: Implications of neuro-glial interaction
2011, NeuropeptidesCitation Excerpt :The development of a morphine tolerance also induces a time-dependent increase in the tissue concentrations of endogenous NOC in the rat periaqueductal gray, amygdala and cerebroventricular perfusate, thereby indicating that a gradual increase in NOC biosynthesis and/or release occurs in these areas (Yuan et al., 1999). Moreover, after an acute administration of an antibody against NOC, both NOC knockout and wildtype mice showed attenuated development of morphine tolerance compared with controls (Chung et al., 2006; Tian and Han, 2000). Also, the development of a tolerance was prevented when NOP antagonist administration preceded a systemic opioid administration.
- 1
Present address: College of Life Sciences, Peking University, Beijing, China.