Neuropharmacology and AnalgesiaEffects of imidazoline I2 receptor ligands on morphine- and tramadol-induced antinociception in rats
Introduction
Pain, both as a symptom and as a disease, imparts high health cost and economic loss to society. Currently available analgesics are not adequate to meet the clinical needs, leaving a big population with undertreated pain. Opioids remain the most effective analgesics for many painful conditions. However, adequate dosing with opioids is limited by unwanted effects, particularly constipation, physical dependence, abuse and overdose. Although great efforts have been made to develop analgesics with novel mechanisms of action for decades, a careful analysis of the analgesics marketed in the past 50 years revealed a lack of clinically significant advances (Kissin, 2010). An alternative strategy is combination therapy, which requires combining two or more drugs for pain management. This scientifically valid strategy has been successfully practiced for treating various diseases including cancer and cardiovascular disorders, and emerging evidence suggests the validity of this strategy for treating pain (Smith, 2008). For example, the combination of a μ opioid agonist with another non-μ opioid analgesic may have increased analgesic effectiveness and/or a better safety profile (Smith, 2008). Further support comes from the finding that analgesic drugs with dual mechanisms of action (μ opioid receptor agonism and a second mechanism) tend to have improved therapeutic profiles. For instance, tramadol is a μ opioid receptor agonist that also enhances serotonin and norepinephrine transmission (Reeves and Burke, 2008). Tramadol is effective in many painful conditions and has relatively low abuse liability, presumably due to this unique pharmacological profile (Epstein et al., 2006). Tapentadol is a μ opioid receptor agonist and a norepinephrine reuptake inhibitor (Hartrick and Rozek, 2011). Clinical studies indicate that tapentadol is effective for both acute and chronic pain and has decreased unwanted effects as compared to μ opioid agonists (Etropolski et al., 2011, Hartrick and Rozek, 2011). Thus, this strategy remains promising for developing candidate analgesics.
Imidazoline receptors are a class of three novel receptors (I1, I2, I3) that are widely distributed in mammalian central and peripheral nervous systems and other tissues (Regunathan and Reis, 1996). Although it is now widely recognized that the imidazoline I1 receptor is involved in central control of blood pressure (Head and Mayorov, 2006), the physiological functions of the I2 receptor are less well-characterized. Accumulating evidence suggests that the I2 receptor is an emerging drug target for novel analgesics (Li and Zhang, 2011). The purported endogenous imidazoline receptor ligand, agmatine, has antinociceptive activity in several animal models of inflammatory and neuropathic pain. Agmatine also increases the antinociceptive effects of morphine in models of both acute and chronic pain (see Li and Zhang, 2011 for review). However, many of the early studies did not examine the receptor mechanisms underlying the antinociceptive effects of agmatine. This is problematic as, besides the I2 receptors, agmatine also binds to several other receptors (Halaris and Plietz, 2007). Nonetheless, agmatine shows analgesic activity in patients with lumbar disc-associated radiculopathy (Keynan et al., 2010). Although selective I2 receptor ligands are available (Dardonville and Rozas, 2004), only two studies have examined the antinociceptive effects of I2 receptor ligands and their interactions with morphine in a mouse model of acute pain and the generality of those findings to other conditions (species, pain models, and opioids) is unknown (Gentili et al., 2006, Sanchez-Blazquez et al., 2000).
The purpose of the current study was to extend previous observations in two important dimensions. First, a single dose is typically used in previous studies and it is unclear the magnitude of the drug interactions. This study exploited full dose–effect functions of both I2 receptor ligands and opioids in an acute pain procedure in a different species. This is important because the potential clinical utility of drug combinations for pain management is based on the robustness of the effect, and a full understanding of the drug interactions can only be achieved by examining the complete dose–effect functions. Second, previous reports exclusively used morphine for the I2 ligand–opioid interaction studies. Because opioids with dual mechanisms (e.g. tramadol and tapentadol) may have favorable therapeutic profiles (Etropolski et al., 2011), and I2 receptor ligands such as 2-BFI and BU224 can modulate brain monoamine transmission (Hudson et al., 1999), it seems warranted to examine the I2 ligand–opioid interactions by using opioids with different mechanisms of action. Thus, the current study examined the interactions between three I2 receptor ligands (2-BFI, BU224, and a non-selective I2 receptor ligand, agmatine) and two opioids (morphine and tramadol) in a warm water tail withdrawal procedure in rats. It was hypothesized that I2 receptor ligands enhanced the antinociceptive effects of the dual mechanism opioid tramadol, and that the magnitude of enhancement was greater for tramadol than for morphine.
Section snippets
Subjects
Adult Sprague–Dawley rats (Harlan, Indianapolis, IN) were housed individually on a 12/12-h light/dark cycle (behavioral experiments were conducted during the light period) with free access to water and food except during experimental sessions. Animals were maintained and experiments were conducted in accordance with the Institutional Animal Care and Use Committee, University at Buffalo, and with the 1996 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources
Results
Under control conditions the average latencies for rats to remove their tails (mean ± SEM, in seconds) from 44°, 48°, and 52 °C water were 20 ± 0 (i.e., the maximal possible effect), 7.79 ± 0.70, and 2.47 ± 0.25, respectively. The baseline latencies did not significantly change throughout the study. Morphine and tramadol dose-dependently increased the latency for rats to remove their tails from 48 °C water (Fig. 1, ED50 [95% CL] = 2.93 [1.62, 5.30] for morphine; ED50 = 31.46 [21.69, 45.63] for tramadol).
Discussion
The primary finding of the present study is that the non-selective I2 receptor ligand agmatine and the selective I2 receptor ligand 2-BFI enhanced the antinociceptive effects of morphine and tramadol. In contrast, the selective I2 receptor ligand BU224 failed to enhance the antinociceptive effects but prevented agmatine and 2-BFI from enhancing morphine and tramadol induced antinociception. These results further reinforce the notion of combining I2 receptor ligands and opioids for pain
Acknowledgments
The authors thank Wonjin Shin for her expert technical assistance.
References (52)
- et al.
Agmatine enhances cannabinoid action in the hot-plate assay of thermal nociception
Pharmacol. Biochem. Behav.
(2009) - et al.
Increase of beta-endorphin secretion by agmatine is induced by activation of imidazoline I(2A) receptors in adrenal gland of rats
Neurosci. Lett.
(2010) - et al.
Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol
Biol. Psychol.
(2006) - 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 I(2)-imidazoline receptors may ameliorate insulin resistance in fructose-rich chow-fed rats
Neurosci. Lett.
(2008) - 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.
Morphine-induced antinociception in the rat: supra-additive interactions with imidazoline I(2) receptor ligands
Eur. J. Pharmacol.
(2011) - et al.
Tramadol is more effective than morphine and amitriptyline against ischaemic pain but not thermal pain in rats
Pharmacol. Res.
(2007)
Agmatine produces antinociception in tonic pain in mice
Pharmacol. Biochem. Behav.
Anti-hypernociceptive properties of agmatine in persistent inflammatory and neuropathic models of pain in mice
Brain Res.
Agmatine potentiates the analgesic effect of morphine by an alpha(2)-adrenoceptor-mediated mechanism in mice
Neuropsychopharmacology
Autoradiographical distribution of imidazoline binding sites in monoamine oxidase A deficient mice
J. Neurochem.
Effect of agmatine on acute and mononeuropathic pain
Ann. N. Y. Acad. Sci.
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.
Controlling pain in the post-operative setting
Int. J. Clin. Pharmacol. Ther.
Agmatine induces antihyperalgesic effects in diabetic rats and a superadditive interaction with R(−)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid, a N-methyl-D-aspartate-receptor antagonist
J. Pharmacol. Exp. Ther.
Imidazoline binding sites and their ligands: an overview of the different chemical structures
Med. Res. Rev.
Comparable efficacy and superior gastrointestinal tolerability (nausea, vomiting, constipation) of tapentadol compared with oxycodone hydrochloride
Adv. Ther.
Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury
Proc. Natl. Acad. Sci. U. S. A.
Analgesic efficacy of CR4056, a novel imidazoline-2 receptor ligand, in rat models of inflammatory and neuropathic pain
J. Pain Res.
Behavioral, neuroendocrine and neurochemical effects of the imidazoline I2 receptor selective ligand BU224 in naive rats and rats exposed to the stress of the forced swim test
Psychopharmacology (Berl)
Antinociceptive effects of monoamine reuptake inhibitors administered alone or in combination with mu opioid agonists in rhesus monkeys
Psychopharmacology (Berl)
Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor
Naunyn Schmiedebergs Arch. Pharmacol.
Agmatine: metabolic pathway and spectrum of activity in brain
CNS Drugs
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