Differential involvement of μ-opioid receptor subtypes in endomorphin-1- and -2-induced antinociception
Introduction
Endomorphin-1 and -2 are tetrapeptide amides isolated from bovine brain, found to have high affinity and selectivity for the μ-opioid receptor, and shown to produce potent and prolonged antinociceptive activity that is reversible by naloxone and β-funaltrexamine (Zadina et al., 1997). There is biochemical and pharmacological evidence supporting the existence of μ-opioid receptor subtypes (Wolozin and Pasternak, 1981; Nishimura et al., 1984; Goodman and Pasternak, 1985). At least two μ-opioid receptor subtypes have been proposed: μ1 and μ2 (Pasternak and Wood, 1986). β-Funaltrexamine irreversibly antagonizes both μ1- and μ2-opioid receptors and inhibits both supraspinal and spinal antinociception, whereas naloxonazine selectively antagonizes the μ1-opioid receptor. It has been suggested that these receptor subtypes have different physiological roles, with μ1-opioid receptors mediating supraspinal antinociception, whereas μ2-opioid receptors mediate spinal antinociception.
In most studies, the method used to measure the antinociceptive effects of opioids is the tail flick test, which depends on tail withdrawal from radiant heat as the noxious stimulus, a response that involves a spinal reflex. The tail flick test does not require the integrative action of the higher brain centers (Irwin et al., 1951). We therefore have studied antinociceptive effects of endomorphins after pretreatment with naloxonazine or β-funaltrexamine on behavior (licking or biting) that requires perception of the noxious stimulus, and integration of behavioral responses, by central (supraspinal) mechanisms. In the present study, the role of the μ-opioid receptor subtypes, μ1 and μ2, in the antinociceptive effects of endomorphins against the response to mechanical noxious stimuli was examined with the irreversible μ1-opioid receptor antagonist, naloxonazine and the irreversible μ1- and μ2-opioid receptor antagonist, β-funaltrexamine.
Section snippets
Materials and methods
Adult male ddY mice weighing 22–25 g were housed in a light- and temperature-controlled room (light on 0900–2100 h; 24°C) and had free access to food and water. Intracerebroventricular (i.c.v.) injections were administered about 2 mm caudal and 2 mm lateral to the bregma at a depth of 3 mm (Haley and McCormick, 1957). The procedure for intrathecal (i.t.) injections was adapted from the method of Hylden and Wilcox (1980)with a constant injection volume of 2 μl/mouse. For i.t. administration, a
Potency and time course of i.c.v. and i.t. injections of endomorphin-1 and -2
The time course of antinociceptive activity for i.c.v. endomorphin-1, -2 and DAMGO is shown in Fig. 1. Groups of mice were tested for antinociception at 1, 3, 5, 10 and 15 min after i.c.v. injection of the endomorphins. Endomorphin-1 and -2 produced dose-dependent antinociception with ED50 values of 1.20 (CL95: 0.68–2.11) nmol, and 1.35 (CL95: 0.70–2.59) nmol, respectively, with maximum effects at 5 min (Fig. 1A,B). Endomorphin-1 had a longer duration of action than endomorphin-2, but the two
Discussion
In this study we showed that both endomorphin-1 and endomorphin-2 induced dose-dependent antinociception after central (i.c.v.) and spinal (i.t.) administration in a test involving central integration of response. The peak effects occurred rapidly, with 5 min for i.c.v. and within 1 min for i.t. injection. The present results of i.t. injected endomorphins are in agreement with those of Stone et al. (1997)who reported that antinociception induced by endomorphin-1 and -2 is short-lasting and is
Acknowledgements
The authors wish to thank Miho Nakayama for her secretarial assistance in preparing the manuscript.
References (22)
- et al.
Intrathecal Tyr-W-MIF-1 produced potent, naloxone-reversible analgesia modulated by α2-adrenoceptors
Eur. J. Pharmacol.
(1996) - et al.
Intrathecal morphine in mice: a new technique
Eur. J. Pharmacol.
(1980) - et al.
Naloxonazine action in vivo
Eur. J. Pharmacol.
(1986) - et al.
Different μ receptor subtypes mediate spinal and supraspinal analgesia in mice
Eur. J. Pharmacol.
(1989) - et al.
Comparison of naloxonazine and β-funaltrexamine antagonism of μ1 and μ2 opioid actions
Life Sci.
(1991) - et al.
Prolonged analgesia after intracerebroventricular Tyr-W-MIF-1 (Tyr- Pro-Trp-Gly-NH2)
Neurosci. Lett.
(1993) - et al.
Binding of Tyr-W-MIF (Tyr-Pro-Trp-Gly-NH2) and related peptides to μ1 and μ2 opiate receptors
Neurosci. Lett.
(1996) - et al.
Cloning and expression of an isoform of the rat μ opioid receptor (rMORIB) which differs in a agonist induced desensitization from rMOR1
FEBS Lett.
(1995) - et al.
Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain
J. Pharmacol. Exp. Ther.
(1998) - et al.
Visualization of mu-1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique
Proc. Natl. Acad. Sci. USA
(1985)
Pharmacological effects produced by intracerebral injections of drugs in the conscious mouse
Br. J. Pharmacol.
Cited by (123)
Synthesis, characterization and nociceptive screening of new VV-hemorphin-5 analogues
2018, Bioorganic and Medicinal Chemistry LettersEffects of neuropeptide FF and related peptides on the antinociceptive activities of VD-hemopressin(α) in naive and cannabinoid-tolerant mice
2015, European Journal of PharmacologyDownregulation of spinal endomorphin-2 correlates with mechanical allodynia in a rat model of tibia cancer
2015, NeuroscienceCitation Excerpt :We infer that reduced spinal EM2 is one important contributor in maintaining CIBP. This notion derives from our observations that i.t. EM2 attenuated pain behavior and WDR neuron excitability, as well as from numerous studies unanimously showing that spinal EM2 exerts analgesic effects (Przewlocka et al., 1999; Sakurada et al., 1999, 2001; Smith et al., 2001). In the present study, i.t. EM2 into CIBP rats alleviated mechanical allodynia and suppressed WDR neuron hyperexcitability elicited by electrical stimulation of C-fibers, suggesting that replenishment of spinal EM2 could remedy these features of CIBP.
Endomorphin-1 and Endomorphin-2: Involvement of Endogenous μ-Opioid Receptor Ligands in Analgesia, Antinociceptive Tolerance, Antianalgesia, and Hyperalgesia
2014, Journal of Experimental and Clinical Medicine (Taiwan)