Neuropharmacology and AnalgesiaMorphine-induced antinociception in the rat: Supra-additive interactions with imidazoline I2 receptor ligands
Introduction
Pain remains a major health problem that markedly reduces quality of life of a large segment of the population and imparts high health costs and economic loss to society. Opioids are the drugs of choice for many pain conditions. However, the unwanted effects related to repeated opioid use including pruritus, constipation and physical dependence limit adequate dosing in the clinic (Annemans, 2011). New analgesics that retain the therapeutic effects but circumvent some of the unwanted effects are in great clinical demand.
One strategy for improved treatment of pain is to combine one opioid with another pharmacologically unrelated drug in the hope that the drug mixture increases the analgesic efficacy while not altering or perhaps diminishing adverse effects of the opioid. However, the practice of this scientifically valid drug development strategy has achieved only modest success thus far (Smith, 2008). For example, opioids in combination with acetaminophen are widely used for pain management. However, the unwanted effects of the drug mixture are similar to those of opioids alone and non-medical use is common (Zacny et al., 2003). This underscores the need to identify new drug targets for analgesic development.
Imidazoline receptors are a group of receptors that recognize compounds with an imidazoline ring, a concept first proposed by Bousquet et al. (1984). Later studies established that the α2 adrenoceptor agonist and imidazoline compound clonidine primarily exerts its hypotensive activity by acting on imidazoline receptors (Head and Mayorov, 2006) and the receptors that have high binding affinity with 3H-para-aminoclonidine and 3Hidazoxan are termed imidazoline I1 receptors (Regunathan and Reis, 1996). Two selective I1 receptor ligands, moxonidine and rilmenidine, are currently used for treating hypertension (Sica, 2007). Imidazoline I2 receptors are binding sites that bind 3H-idazoxan and 3H-2-BFI with high affinity and 3H-para-aminoclonidine and 3H-clonidine with much lower affinity (Regunathan and Reis, 1996). Imidazoline I2 receptors might be implicated in several psychiatric disorders including depression, opioid addiction and neurodegenerative diseases as the density of I2 receptors is significantly different in patients who suffer from those disorders as compared to control (Garcia-Sevilla et al., 1999). However, the possible functional relationship between I2 receptors and these disorders remains to be elucidated (Garcia-Sevilla et al., 1999). Autoradiographical studies indicate that I2 receptors are widely distributed in the central nervous systems, with high bindings to the area postrema, interpeduncular nucleus, arcuate nucleus, mammillary peduncle, ependyma and pineal gland (Lione et al., 1998). Emerging evidence indicates that the cationic polyamine, agmatine, possesses antinociceptive and analgesic activity both in animals and in man (Li and Zhang, 2011). Agmatine is a non-selective low-affinity imidazoline I1 and I2 receptor ligand but also has affinity for α2 adrenoceptors, NMDA receptors, and nicotinic receptors, and also inhibits nitric oxide production (Berkels et al., 2004, Loring, 1990). The mechanisms of the antinociceptive effects of agmatine primarily involve I2 receptors and α2 adrenoceptors (Li et al., 1999, Roerig, 2003). Although the antinociceptive effects of α2 adrenoceptor agonists are well established, there are only limited data concerning the antinociceptive effects of I2 receptor ligands, and few studies employ selective I2 receptor ligands (Gentili et al., 2006, Sanchez-Blazquez et al., 2000).
Consistent with the effects of agmatine, selective I2 receptor ligands enhance the antinociceptive effects of morphine and attenuate the development of tolerance to morphine antinociception for pain following thermal stimulation (Boronat et al., 1998, Sanchez-Blazquez et al., 2000). However, previous studies only employed one procedure (radiant tail flick) and a single dose is typically used. Thus, it is unclear of the extent to which these findings relate to other models of pain and the nature of the interaction between I2 receptors and opioid receptors. This study investigated the antinociceptive effects of agmatine, morphine and two selective I2 receptor ligands 2-BFI and BU224 (Fig. 1) using a hypertonic saline-induced writhing test in the rat. Furthermore, potential receptor mechanisms were explored using pharmacological antagonists and the application of quantitative pharmacological analysis.
Section snippets
Subjects
Two groups of adult male Sprague–Dawley rats (Harlan, Indianapolis, IN) were housed individually under a 12/12-h light/dark cycle beginning at 6:00 a.m. (experiments were conducted during the light period) with free access to standard rodent chow and water in the home cage. One group of 9 rats contributed to the data shown in Fig. 2, Fig. 3, Fig. 4 and a second group of 8 rats contributed to the data of Fig. 5, Fig. 6. Animals were maintained and experiments were conducted in accordance with
Results
The hypertonic (5%) saline-induced writhing response was stable within sessions. The writhing response for both groups of rats was examined at the beginning and the completion of the study and the percentage of rats demonstrating writhing response for four consecutive 20-min cycles were (mean ± S.E.M.): 89% ± 7.9%, 94% ± 3.4%, 92% ± 5.3% and 88% ± 0.4%.
Morphine and the selective imidazoline I2 receptor ligands, 2-BFI and BU224, produced antinociceptive effects in a dose-related manner (Fig. 2; see Table 1
Discussion
The primary finding of the current study is that the selective imidazoline I2 receptor ligands, 2-BFI and BU224, alone had antinociceptive effects and in combination with morphine produced antinociceptive effects in a supra-additive manner in a writhing test. Pharmacological antagonism studies indicate that the effects of 2-BFI and BU224 were mediated by I2 receptors but not by α2 adrenoceptors. In contrast, the non-selective I2 receptor ligand/α2 adrenoceptor agonist agmatine alone did not
Acknowledgments
The authors thank Wonjin Shin for her expert technical assistance. None of the authors has any conflict of interest with this work.
References (43)
- et al.
Agmatine enhances cannabinoid action in the hot-plate assay of thermal nociception
Pharmacol. Biochem. Behav.
(2009) - et al.
Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis
Pharmacol. Ther.
(2009) - et al.
Involvement of I2-imidazoline binding sites in positive and negative morphine analgesia modulatory effects
Eur. J. Pharmacol.
(2006) - et al.
Direct oxidative conversion of aldehydes and alcohols to 2-imidazolines and 2-oxazolines using molecular iodine
Tetrahedron
(2007) - et al.
Activation of imidazoline receptor by agmatine to lower plasma glucose in streptozotocin-induced diabetic rats
Neurosci. Lett.
(2004) - et al.
Modulation of opioid analgesia by agmatine
Eur. J. Pharmacol.
(1996) - et al.
Imidazoline I(2) receptors: target for new analgesics?
Eur. J. Pharmacol.
(2011) - et al.
Effects of serotonin (5-HT)1A and 5-HT2A receptor agonists on schedule-controlled responding in rats: drug combination studies
Psychopharmacology (Berl)
(2011) - et al.
Characterisation and localisation of [3H]2-(2-benzofuranyl)-2-imidazoline binding in rat brain: a selective ligand for imidazoline I2 receptors
Eur. J. Pharmacol.
(1998) Serotonin and pain: evidence that activation of 5-HT1A receptors does not elicit antinociception against noxious thermal, mechanical and chemical stimuli in mice
Pain
(1994)
Agmatine blocks morphine-evoked hyperthermia in rats
Brain Res.
Activation of I2-imidazoline receptors by agmatine improved insulin sensitivity through two mechanisms in type-2 diabetic rats
Neurosci. Lett.
College on problems of drug dependence taskforce on prescription opioid non-medical use and abuse: position statement
Drug Alcohol Depend.
Pharmacoeconomic impact of adverse events of long-term opioid treatment for the management of persistent pain
Clin. Drug Investig.
Agmatine signaling: odds and threads
Cardiovasc. Drug Rev.
Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands
Br. J. Pharmacol.
Central cardiovascular effects of alpha adrenergic drugs: differences between catecholamines and imidazolines
J. Pharmacol. Exp. Ther.
The abdominal constriction response and its suppression by analgesic drugs in the mouse
Br. J. Pharmacol. Chemother.
A method for evaluating analgesic agents in rats
J. Pharmacol. Methods
Imidazoline receptors and human brain disorders
Ann. N. Y. Acad. Sci.
Agmatine: metabolic pathway and spectrum of activity in brain
CNS Drugs
Cited by (37)
α<inf>2</inf>-agonists and antagonists
2022, Small Animal Critical Care MedicineCombining opioids and non-opioids for pain management: Current status
2019, NeuropharmacologyProtective effect of the imidazoline I2 receptor agonist 2-BFI on oxidative cytotoxicity in astrocytes
2018, Biochemical and Biophysical Research CommunicationsImidazoline I<inf>2</inf> receptors: An update
2017, Pharmacology and TherapeuticsCitation Excerpt :Three studies examined the antinociceptive effects of I2 receptor ligands in chemical stimulation-induced pain models. In a rat model of hypertonic saline-induced writhing test, 2-BFI, BU224 and morphine were equally effective in decreasing the writhing response (Li, Zhang, & Winter, 2011). Importantly, the antinociceptive effects were antagonized by idazoxan, suggesting that the effect was mediated by I2 receptors.
Design, synthesis and biological evaluation of novel analgesic agents targeting both cyclooxygenase and TRPV1
2016, Bioorganic and Medicinal ChemistryDiscriminative stimulus effects of the imidazoline I<inf>2</inf> receptor ligands BU224 and phenyzoline in rats
2015, European Journal of PharmacologyCitation Excerpt :In general, decreasing the training dose decreases pharmacologic selectivity and the efficacy requirements of the assay. In the current study and previous studies using 2-BFI as the training drug, the training doses of 2-BFI and BU224 do not affect the rate of operant responding, although they are behaviorally active (i.e., antinociception) (Li et al., 2014, 2011). Substantially larger doses of 2-BFI (10 mg/kg) and BU224 (17.8 mg/kg) can significantly suppress food-maintained operant responding under the same schedule of reinforcement (An et al., 2012).