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Available online at www.sciencedirect.com
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Research Report
Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors Q1
Daniela da Fonseca Pacheco1, Thiago Roberto Lima Romero1, Igor Dimitri Gama Duarten Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6627, CEP 31.270.100, Belo Horizonte, Brazil
art i cle i nfo
ab st rac t
Article history:
It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic
Accepted 14 March 2014
and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic
Keywords:
cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that
Ketamine
at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal
Endogenous opioid
antinociception. In this study, we investigated the involvement of endogenous opioids in
Central antinociception
ketamine-induced central antinociception. The nociceptive threshold for thermal stimulation was measured in Swiss mice using the tail-flick test. The drugs were administered via the intracerebroventricular route. Our results demonstrated that the opioid receptor antagonist naloxone, the μ-opioid receptor antagonist clocinnamox and the δ-opioid receptor antagonist naltrindole, but not the κ-opioid receptor antagonist nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner. Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect. & 2014 Published by Elsevier B.V.
1.
Introduction
Ketamine has been used clinically as an anesthetic for over 40 years, and it is also known to produce analgesic effects for acute and chronic pain in humans and animals (Eichenberger Q2
et al., 2008; Parsons et al., 1993). It is well known that ketamine inhibits glutamatergic N-methyl-d-aspartate (NMDA) receptors in a noncompetitive manner (Lodge and Johnson, 1990). Intrathecal and/or systemic ketamine administration potently reduces hyperalgesia, spontaneous
n Correspondence to: Departamento de Farmacologia, ICB-UFMG, Av. Antônio Carlos, 6627 – Campus da Pampulha, CEP 31.270-100, Belo Horizonte, MG, Brazil. Fax: þ55 31 409 2695. E-mail address: [email protected] (I.D.G. Duarte). 1 Both authors Pacheco and Romero have the same participation.
http://dx.doi.org/10.1016/j.brainres.2014.03.026 0006-8993/& 2014 Published by Elsevier B.V.
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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pain-related behavior, and intraplantar formalin-evoked spinal dorsal horn neuronal responses, likely because of NMDA receptor inhibition (Haley et al., 1990; Qian et al., 1996; Ren et al., 1992; Yamamoto and Yaksh, 1992). Although is generally believed that NMDA receptor antagonism accounts for most of its anesthetic and some of its analgesic effects, ketamine interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors (Kohrs and Durieux, 1998). Opioid and NMDA receptors and their endogenous ligands are found in large concentrations in areas of the central nervous system. The periaqueductal gray area (PAG) contains high concentrations of endogenous opioid peptides β-endorphin and Met-enkephalin and opioid receptors μ and δ. Activation of any of these opioid receptors by β-endorphin, morphine or other opioids administered into the PAG produces potent antinociception at supraspinal sites (Terashvili et al., 2008). It has been reported that β-endorphin injected supraspinally activates the descending pain control pathway, which involves the release of Met-enkephalin acting on μand δ-opioid receptors in the spinal cord for producing antinociception (Tseng, 2001). On the other hand, it has been demonstrated the presence of NMDA receptors at both spinal levels within the dorsal horn and at supraspinal levels (brainstem, thalamus and cortex) involved in nociceptive transmission (Kalb and Fox, 1997). Few studies have assessed the involvement and contribution of the opioid receptors in generating ketamine-induced effects. It was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. This finding comes from the fact that intraperitoneal ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in μ-opioid receptor knockout mice smaller compared with those in wild-type animals (Sarton et al., 2001). At the spinal level, intrathecal administration of ketamine significantly enhances endogenous opioid-induced antinociception (Horvath et al., 2001). Additionally, spinal ketamine-induced antinociception is antagonized by opioid receptor antagonist
naloxone, indicating that endogenous opioids might be involved in this effect (Crisp et al., 1991; Pekoe and Smith, 1982). In contrast, intramuscular administration of ketamine failed to selectively enhance μ opioid receptor agonist fentanyl-induced thermal antinociception (Banks et al., 2010). This finding adds to a growing preclinical literature reporting equivocal results with ketamine and other noncompetitive NMDA antagonists as adjuncts to opioid agonists (Hoffmann et al., 2003). To elucidate the mechanisms involved in the central ketamine administration, in the present study, we investigated whether endogenous opioids are involved in central ketamine-induced antinociception and the opioid receptors involved.
2.
Results
2.1.
Antinociceptive effect of ketamine
The intracerebroventricular administration of ketamine (2, 4 and 8 μg) produced an antinociceptive response, in a dose-dependent manner (Fig. 1). There was no statistical difference between the 8 and 4 μg doses, being the dose of 4 μg chosen for the present study.
2.2. Antagonism of ketamine-induced antinociception by naloxone, clocinnamox or naltrindole As shown in Fig. 2a, b and c, the intracerebroventricular administration of naloxone (2.5 and 5 μg), clocinnamox (2 and 4 μg) or naltrindole (6 and 12 μg) inhibited the ketamineinduced central antinociception (4 μg), respectively. The highest effective dose of the antagonists did not significantly modify the nociceptive threshold in control mice (Fig. 2a–c).
2.3. Effect of nor-binaltorphimine on ketamine-induced antinociception The intracerebroventricular administration of nor-binaltorphimine (10 and 20 μg) did not modify the central antinociception of ketamine (4 μg; Fig. 3). This drug did not significantly modify the nociceptive threshold in control mice.
2.4. Increase of ketamine-induced antinociception by bestatin Bestatin (20 μg) administration enhanced the central antinociception induced by a low dose of ketamine (2 μg; Fig. 4). Bestatin alone did not induce any effect.
Fig. 1 – Antinociception induced by intracerebroventricular administration of ketamine in mice. Ketamine (Ket; 2, 4 and 8 μg) was administered 5 min prior to measured in the tail-flick test. Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to Saline-injected group (ANOVAþBonferroni's test; interaction: F(12, 64)¼ 15.78; time: F(4, 64)¼ 82.09; treatment: F(3, 16)¼ 45.01; po0.0001; n ¼ 5). Saline (0.5% of Evans Blue).
3.
Discussion
The importance of opioids in pain control is undisputed, and the antinociceptive effects are caused by opioid receptor activation at supraspinal, spinal, and peripheral levels (Khalefa et al., 2012). Recently, our group demonstrated that endogenous opioids participate in the mechanism of action of several drugs (Guzzo et al., 2012; Reis et al., 2009;
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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Fig. 2 – Antagonism induced by intracerebroventricular administration of naloxone (a), clocinnamox (b) or naltrindole (c) on the central antinociception produced by ketamine. Naloxone (Nal; 2.5 and 5 μg), clocinnamox (Clo; 2 and 4 μg) or naltrindole (NTD; 6 and 12 μg) were administered 1 min prior to ketamine (Ket; 4 μg). These antagonists did not significantly modify the nociceptive threshold in control mice. Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to (SalþSal)-injected group and # indicates a significant difference compared to (SalþKet 4)-injected group (ANOVAþBonferroni's test; interaction: F(16, 80) ¼19.25; time: F(4, 80)¼ 44.16; treatment: F(4, 20)¼ 24.69; po0.0001; n ¼ 5 (a); interaction: F(16, 80) ¼9.06; time: F(4, 80) ¼39.30; treatment: F(4, 20)¼ 21.77; po0.0001; n ¼5 (b); interaction: F(16, 80)¼ 12.52; time: F(4, 80)¼ 46.29; treatment: F(4, 20)¼ 25.22; po0.0001; n ¼ 5 (c)). Sal – saline (0.5% of Evans Blue).
Fig. 3 – Effect of intracerebroventricular administration of nor-binaltorphimine on the central antinociception produced by ketamine. Nor-binaltorphimine (NorBni; 10 and 20 μg) was administered 1 min prior to the ketamine (Ket; 4 μg). Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to Sal-injected group respectively (ANOVAþBonferroni's test; interaction: F(16, 80)¼ 17.69; time: F(4, 80) ¼78.64; treatment: F(4, 20) ¼85.51; po0.0001; n¼ 5). Sal – saline (0.5% of Evans Blue).
Romero et al., 2009, 2013). In this work, we investigated the participation these peptides in ketamine-induced central antinociception.
Fig. 4 – Potentiation of ketamine-induced antinociception by bestatin. The bestatin (Bes; 20 μg) was administered 1 min prior to ketamine (Ket; 4 μg). This drug alone did not induce any effect. Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to (SalþSal)-injected group and ♯ indicates a significant difference compared to (SalþKet 2)-injected group (ANOVAþBonferroni's test; interaction: F(12, 64) ¼28.46; time: F(4, 64) ¼49.72; treatment: F(3, 16)¼ 103.00; po0.0001; n ¼5). Sal – saline (0.5% of Evans Blue).
Initially, the ability of ketamine to induce central antinociception was investigated with the tail-flick test. As with all reflexes, the tail-flick is subject to control by supraspinal
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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structures (Le Bars et al., 2001) and has been useful in identifying the site of action of analgesics and other drugs upon the supraspinal centers involved in nociception (Leandri et al., 2011; Pacheco et al., 2009; Romero et al., 2013). It is well known that ketamine inhibits N-methyl-d-aspartate (NMDA) receptors in a noncompetitive manner (Lodge and Johnson, 1990). Functional studies suggest that NMDA receptors participate in the transmission of nociceptive signals (Mao, 1999), and glutamate action, particularly on NMDA receptors, is of importance to both acute and chronic pain transmission (Lutfy et al., 1997; Millan, 1999). Additionally, anatomical studies have demonstrated the presence of NMDA receptors at both spinal levels within the dorsal horn and at supraspinal levels (brainstem, thalamus and cortex) involved in nociceptive transmission (Kalb and Fox, 1997). Our results showed that ketamine produced a central antinociceptive effect in a dose-dependent manner; thus, a 4 μg dose was chosen for the present study. NMDA receptor antagonists produce variable effects in the tail-flick test, and the mechanisms underlying ketamine-mediated central antinociception remain controversial. For example, the systemic or intrathecal ketamine administration produced antinociception in this test (Baumeister and Advokat, 1991). In contrast, some authors suggest that selective NMDA receptor antagonists administered in mice are ineffective in the tail-flick test (Goettl and Larson, 1994; Näsström et al., 1992). Importantly, NMDA receptor antagonism accounts for most of the anesthetic and some of the analgesic effects of ketamine; however, ketamine interacts at multiple sites, such as NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors within the central nervous system (Kohrs and Durieux, 1998). There are three main types of opioid receptors, namely μ, δ and κ (Singh et al., 1997). The periaqueductal gray area (PAG) contains high concentrations of endogenous opioid peptides β-endorphin and enkephalin and receptors μ and δ (Yaksh et al., 1988). Activation of any of these opioid receptors by PAG administration of β-endorphin, morphine or other opioids produces potent antinociception at supraspinal sites and also activates the descending pain control pathways, which are mediated by the brainstem rostral ventromedial medulla (RVM) (Basbaum and Fields, 1984; Pavlovic and Bodnar, 1998; Smith et al., 1988). The RVM contains μ-, δ-, and κ-opioid receptors and it is a major locus for the descending control of nociception and opioid analgesia (Bowker and Dilts, 1988; Gutstein et al., 1998; Kalyuzhny and Wessendorf, 1998). Importantly, the tail-flick response is modulated in the RVM (Gilbert and Franklin, 2001). According to Sarton et al. (2001), ketamine interacts with the μopioid system and produces supraspinal antinociception (Sarton et al., 2001). It enhances opioid-induced analgesic signaling by modulating phosphorylation in cells that endogenously express μ-opioid receptors (Gupta et al., 2011). Additionally, ketamine-mediated spinal antinociception is antagonized by the opioid receptor antagonist naloxone, indicating that endogenous opioids might be involved (Crisp et al., 1991; Pekoe and Smith, 1982). Furthermore, ketamineinduced potentiation of morphine analgesia was completely abolished by naloxone (Campos et al., 2006). Likewise, our results demonstrated that naloxone inhibited central
ketamine-induced antinociception in a dose-dependent manner. This may be a direct effect on the μ opioid receptor or an indirect effect via release of endogenous opioid peptides that act on opioid receptors. Naloxone has been useful for receptor affinity determination of type-selective opioids in mammals; however, though it preferentially interacts with μ binding sites (KD ¼3.9 nM), it also has significant affinity for κ-opioid receptors (KD ¼ 16 nM) and a lesser affinity for δ-opioid receptors (KD ¼ 95 nM) (Satoh and Minami, 1995). To clarify which receptor subtype would be involved in ketamine-mediated central antinociception, highly selective antagonists were used, namely clocinnamox, naltrindole and nor-binaltorphimine. Clocinnamox is an irreversible μopioid receptor antagonist with apparent Ki values of 0.7, 1.9 and 5.7 nM for mouse μ, δ and κ receptors, respectively (Burke et al., 1994). Naltrindole has 223- and 346-fold greater activity for δ than for μ and κ opioid receptors (Portoghese et al., 1990), and nor-binaltorphimine is 27- to 29-fold less potent, respectively, for μ and δ binding sites compared with κ receptor binding sites (Rothman et al., 1988). The results demonstrated that clocinnamox and naltrindole, but not- nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner, suggesting the participation of μ and δ opioid receptors in this effect. Accordingly, the PAG has a high concentration of opioid receptors μ and δ (Yaksh et al., 1988). In contrast, it was demonstrated that the ketamine potentiate the antinociceptive effects of μ- but not δ- or κ-opioid agonists in a mouse model of acute pain (Baker et al., 2002). In order to add more data about the action of naloxone, clocinnamox and naltrindole in this work, bestatin, an aminopeptidase inhibitor that cleaves enkephalin at the tyrosylglycine bond (Hersh, 1982; Jia et al., 2010), was used. In vivo, enkephalins appear to be degraded by enzymes such as neutral endopeptidase and aminopeptidase (Roques et al., 1993). It was shown that intravenous injection of RB101, a dual inhibitor of enkephalinases, significantly reduced the total number of carrageenan-evoked c-Fos-immunoreactivity nuclei in the spinal cord and that this effect was blocked by mand κ-opioid receptor antagonists administration, suggesting that in enkephalin-induced antinociception, functional interactions between opioid receptors may occur (Le Guen et al., 2003). Other opioid peptides, such as β-endorphin or dynorphin, appear to be resistant to neutral endopeptidase and, to a lesser extent, aminopeptidase (Nieto et al., 2001). Our data demonstrated that bestatin administration increased low-dose (5 μg) ketamine-induced central antinociception, suggesting endogenous opioid peptide mobilization. Really, peptidases are capable of limiting the activation of μ-opioid receptors in the dorsal horn by physiologically released opioids and supports evidence that inhibitors of opioid-degrading peptidases have valuable analgesic properties (Roques, 2000). Additionally, pilot experiments performed by our group showed that clocinnamox and naltrindole prevent the enhanced ketamine antinociception by bestatin (data not shown). In conclusion, our results suggest that the central antinociceptive effect of ketamine is associated with endogenous opioid release that acts on μ and δ opioid receptors. The results of this work contribute to a greater understanding of the central antinociceptive mechanisms of a drug widely
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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used in veterinary therapy; however, more work needs to be done to elucidate the relationship between ketamine and endogenous opioids.
4.
Experimental procedures
4.1.
Animals
substance was assessed in pilot experiments and literature data (Romero et al., 2013). The nociceptive threshold was always measured in the mouse tail and the measurements of latency were performed at the following times: 0, 5, 10, 15 and 30 min.
4.5.
The experiments were performed on 25–30 g male Swiss mice (n¼ 5 per group) from the CEBIO (The Animal Centre) of the University of Minas Gerais (UFMG). The mice were housed in a temperature-controlled room (2371 1C) on an automatic 12-h light/dark cycle (06:00–18:00 h of light phase). All testing was carried out during the light phase (08:00–15:00 h). Food and water were freely available until the onset of the experiments. The algesimetric protocol was approved by the Ethics Committee on Animal Experimentation (CETEA) of UFMG.
4.2.
Algesimetric method
The tail-flick test used in the present study was conducted in accordance with the procedure described by D'Amour and Smith (1941) with a slight modification. Briefly, following restraining of the mouse by one of experimenter's hand, a heat source was applied 2 cm from the tip of the tail, and the time(s) required for the animal to withdraw its tail from the heat source was recorded as the tail-flick latency. The intensity of the heat was adjusted so that the baseline latencies were between 3 and 4 s. To avoid tissue damage, the cut-off time was established at 9 s. The baseline latency was obtained for each animal before drug administration (zero time) by calculating an average of three consecutive trials. To reduce stress, mice were habituated to the apparatus 1 day prior to conducting the experiments.
4.3.
Intracerebroventricular injection (i.c.v.)
Animals were constrained by a special device, which immobilizes their body, except for their head. With one hand the experimenter restrained the animal head and then injected the drugs into its right lateral ventricle, by intracerebroventricular route using a Hamilton syringe of 5 μl. The site of injection was 1 mm from either side of the midline on a line Q3 drawn through the anterior base of the ears (modified from Haley and Mccormick (1957)). The syringe was inserted perpendicularly through the skull into the brain in the profundity of 2 mm and 2 μl of solution was injected. For ascertaining the areas in the brain ventricular system into which the drugs penetrated, dilution of the drugs in Evans blue 0.5% was realized and the brain were sectioned for confirmation after experiments under anesthesia.
4.4.
Experimental protocol
All drugs were i.c.v. administered into the lateral ventricle. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine and bestatin were administered 1 min prior to the ketamine. The protocol to determine the best moment for the injection of each
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Statistical analysis
Data were analyzed statistically by Repeated Measures ANOVA with post-hoc Bonferroni's test for multiple comparisons. Probabilities less than 5% (Po0.05) were considered to be statistically significant.
4.6.
Chemicals
The following drugs and chemicals were used: ketamine (Sigma, USA), opioid receptor antagonist naloxone (Sigma), μ opioid receptor antagonist clocinnamox (Tocris, USA), δ opioid receptor antagonist naltrindole (Tocris), κ-opioid receptor antagonist nor-binaltorphimine (Sigma) and aminopeptidase inhibitor bestatin (Sigma). All drugs were dissolved in saline and injected in a volume of 2 μl into the lateral ventricle. The saline used for dilution of all drugs contained a 0.5% of Evans Blue.
Conflicts of interest The authors state no conflict of interest.
Acknowledgments Fellowship by Conselho Nacional de Pesquisa (CNPq).
r e f e r e nc e s
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Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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Research Report
Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors Q1
Daniela da Fonseca Pacheco1, Thiago Roberto Lima Romero1, Igor Dimitri Gama Duarten Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6627, CEP 31.270.100, Belo Horizonte, Brazil
art i cle i nfo
ab st rac t
Article history:
It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic
Accepted 14 March 2014
and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic
Keywords:
cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that
Ketamine
at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal
Endogenous opioid
antinociception. In this study, we investigated the involvement of endogenous opioids in
Central antinociception
ketamine-induced central antinociception. The nociceptive threshold for thermal stimulation was measured in Swiss mice using the tail-flick test. The drugs were administered via the intracerebroventricular route. Our results demonstrated that the opioid receptor antagonist naloxone, the μ-opioid receptor antagonist clocinnamox and the δ-opioid receptor antagonist naltrindole, but not the κ-opioid receptor antagonist nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner. Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect. & 2014 Published by Elsevier B.V.
1.
Introduction
Ketamine has been used clinically as an anesthetic for over 40 years, and it is also known to produce analgesic effects for acute and chronic pain in humans and animals (Eichenberger Q2
et al., 2008; Parsons et al., 1993). It is well known that ketamine inhibits glutamatergic N-methyl-d-aspartate (NMDA) receptors in a noncompetitive manner (Lodge and Johnson, 1990). Intrathecal and/or systemic ketamine administration potently reduces hyperalgesia, spontaneous
n Correspondence to: Departamento de Farmacologia, ICB-UFMG, Av. Antônio Carlos, 6627 – Campus da Pampulha, CEP 31.270-100, Belo Horizonte, MG, Brazil. Fax: þ55 31 409 2695. E-mail address: [email protected] (I.D.G. Duarte). 1 Both authors Pacheco and Romero have the same participation.
http://dx.doi.org/10.1016/j.brainres.2014.03.026 0006-8993/& 2014 Published by Elsevier B.V.
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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pain-related behavior, and intraplantar formalin-evoked spinal dorsal horn neuronal responses, likely because of NMDA receptor inhibition (Haley et al., 1990; Qian et al., 1996; Ren et al., 1992; Yamamoto and Yaksh, 1992). Although is generally believed that NMDA receptor antagonism accounts for most of its anesthetic and some of its analgesic effects, ketamine interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors (Kohrs and Durieux, 1998). Opioid and NMDA receptors and their endogenous ligands are found in large concentrations in areas of the central nervous system. The periaqueductal gray area (PAG) contains high concentrations of endogenous opioid peptides β-endorphin and Met-enkephalin and opioid receptors μ and δ. Activation of any of these opioid receptors by β-endorphin, morphine or other opioids administered into the PAG produces potent antinociception at supraspinal sites (Terashvili et al., 2008). It has been reported that β-endorphin injected supraspinally activates the descending pain control pathway, which involves the release of Met-enkephalin acting on μand δ-opioid receptors in the spinal cord for producing antinociception (Tseng, 2001). On the other hand, it has been demonstrated the presence of NMDA receptors at both spinal levels within the dorsal horn and at supraspinal levels (brainstem, thalamus and cortex) involved in nociceptive transmission (Kalb and Fox, 1997). Few studies have assessed the involvement and contribution of the opioid receptors in generating ketamine-induced effects. It was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. This finding comes from the fact that intraperitoneal ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in μ-opioid receptor knockout mice smaller compared with those in wild-type animals (Sarton et al., 2001). At the spinal level, intrathecal administration of ketamine significantly enhances endogenous opioid-induced antinociception (Horvath et al., 2001). Additionally, spinal ketamine-induced antinociception is antagonized by opioid receptor antagonist
naloxone, indicating that endogenous opioids might be involved in this effect (Crisp et al., 1991; Pekoe and Smith, 1982). In contrast, intramuscular administration of ketamine failed to selectively enhance μ opioid receptor agonist fentanyl-induced thermal antinociception (Banks et al., 2010). This finding adds to a growing preclinical literature reporting equivocal results with ketamine and other noncompetitive NMDA antagonists as adjuncts to opioid agonists (Hoffmann et al., 2003). To elucidate the mechanisms involved in the central ketamine administration, in the present study, we investigated whether endogenous opioids are involved in central ketamine-induced antinociception and the opioid receptors involved.
2.
Results
2.1.
Antinociceptive effect of ketamine
The intracerebroventricular administration of ketamine (2, 4 and 8 μg) produced an antinociceptive response, in a dose-dependent manner (Fig. 1). There was no statistical difference between the 8 and 4 μg doses, being the dose of 4 μg chosen for the present study.
2.2. Antagonism of ketamine-induced antinociception by naloxone, clocinnamox or naltrindole As shown in Fig. 2a, b and c, the intracerebroventricular administration of naloxone (2.5 and 5 μg), clocinnamox (2 and 4 μg) or naltrindole (6 and 12 μg) inhibited the ketamineinduced central antinociception (4 μg), respectively. The highest effective dose of the antagonists did not significantly modify the nociceptive threshold in control mice (Fig. 2a–c).
2.3. Effect of nor-binaltorphimine on ketamine-induced antinociception The intracerebroventricular administration of nor-binaltorphimine (10 and 20 μg) did not modify the central antinociception of ketamine (4 μg; Fig. 3). This drug did not significantly modify the nociceptive threshold in control mice.
2.4. Increase of ketamine-induced antinociception by bestatin Bestatin (20 μg) administration enhanced the central antinociception induced by a low dose of ketamine (2 μg; Fig. 4). Bestatin alone did not induce any effect.
Fig. 1 – Antinociception induced by intracerebroventricular administration of ketamine in mice. Ketamine (Ket; 2, 4 and 8 μg) was administered 5 min prior to measured in the tail-flick test. Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to Saline-injected group (ANOVAþBonferroni's test; interaction: F(12, 64)¼ 15.78; time: F(4, 64)¼ 82.09; treatment: F(3, 16)¼ 45.01; po0.0001; n ¼ 5). Saline (0.5% of Evans Blue).
3.
Discussion
The importance of opioids in pain control is undisputed, and the antinociceptive effects are caused by opioid receptor activation at supraspinal, spinal, and peripheral levels (Khalefa et al., 2012). Recently, our group demonstrated that endogenous opioids participate in the mechanism of action of several drugs (Guzzo et al., 2012; Reis et al., 2009;
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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Fig. 2 – Antagonism induced by intracerebroventricular administration of naloxone (a), clocinnamox (b) or naltrindole (c) on the central antinociception produced by ketamine. Naloxone (Nal; 2.5 and 5 μg), clocinnamox (Clo; 2 and 4 μg) or naltrindole (NTD; 6 and 12 μg) were administered 1 min prior to ketamine (Ket; 4 μg). These antagonists did not significantly modify the nociceptive threshold in control mice. Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to (SalþSal)-injected group and # indicates a significant difference compared to (SalþKet 4)-injected group (ANOVAþBonferroni's test; interaction: F(16, 80) ¼19.25; time: F(4, 80)¼ 44.16; treatment: F(4, 20)¼ 24.69; po0.0001; n ¼ 5 (a); interaction: F(16, 80) ¼9.06; time: F(4, 80) ¼39.30; treatment: F(4, 20)¼ 21.77; po0.0001; n ¼5 (b); interaction: F(16, 80)¼ 12.52; time: F(4, 80)¼ 46.29; treatment: F(4, 20)¼ 25.22; po0.0001; n ¼ 5 (c)). Sal – saline (0.5% of Evans Blue).
Fig. 3 – Effect of intracerebroventricular administration of nor-binaltorphimine on the central antinociception produced by ketamine. Nor-binaltorphimine (NorBni; 10 and 20 μg) was administered 1 min prior to the ketamine (Ket; 4 μg). Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to Sal-injected group respectively (ANOVAþBonferroni's test; interaction: F(16, 80)¼ 17.69; time: F(4, 80) ¼78.64; treatment: F(4, 20) ¼85.51; po0.0001; n¼ 5). Sal – saline (0.5% of Evans Blue).
Romero et al., 2009, 2013). In this work, we investigated the participation these peptides in ketamine-induced central antinociception.
Fig. 4 – Potentiation of ketamine-induced antinociception by bestatin. The bestatin (Bes; 20 μg) was administered 1 min prior to ketamine (Ket; 4 μg). This drug alone did not induce any effect. Each line represents the mean7SEM for 5 mice per group. * Indicates a significant difference compared to (SalþSal)-injected group and ♯ indicates a significant difference compared to (SalþKet 2)-injected group (ANOVAþBonferroni's test; interaction: F(12, 64) ¼28.46; time: F(4, 64) ¼49.72; treatment: F(3, 16)¼ 103.00; po0.0001; n ¼5). Sal – saline (0.5% of Evans Blue).
Initially, the ability of ketamine to induce central antinociception was investigated with the tail-flick test. As with all reflexes, the tail-flick is subject to control by supraspinal
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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structures (Le Bars et al., 2001) and has been useful in identifying the site of action of analgesics and other drugs upon the supraspinal centers involved in nociception (Leandri et al., 2011; Pacheco et al., 2009; Romero et al., 2013). It is well known that ketamine inhibits N-methyl-d-aspartate (NMDA) receptors in a noncompetitive manner (Lodge and Johnson, 1990). Functional studies suggest that NMDA receptors participate in the transmission of nociceptive signals (Mao, 1999), and glutamate action, particularly on NMDA receptors, is of importance to both acute and chronic pain transmission (Lutfy et al., 1997; Millan, 1999). Additionally, anatomical studies have demonstrated the presence of NMDA receptors at both spinal levels within the dorsal horn and at supraspinal levels (brainstem, thalamus and cortex) involved in nociceptive transmission (Kalb and Fox, 1997). Our results showed that ketamine produced a central antinociceptive effect in a dose-dependent manner; thus, a 4 μg dose was chosen for the present study. NMDA receptor antagonists produce variable effects in the tail-flick test, and the mechanisms underlying ketamine-mediated central antinociception remain controversial. For example, the systemic or intrathecal ketamine administration produced antinociception in this test (Baumeister and Advokat, 1991). In contrast, some authors suggest that selective NMDA receptor antagonists administered in mice are ineffective in the tail-flick test (Goettl and Larson, 1994; Näsström et al., 1992). Importantly, NMDA receptor antagonism accounts for most of the anesthetic and some of the analgesic effects of ketamine; however, ketamine interacts at multiple sites, such as NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors within the central nervous system (Kohrs and Durieux, 1998). There are three main types of opioid receptors, namely μ, δ and κ (Singh et al., 1997). The periaqueductal gray area (PAG) contains high concentrations of endogenous opioid peptides β-endorphin and enkephalin and receptors μ and δ (Yaksh et al., 1988). Activation of any of these opioid receptors by PAG administration of β-endorphin, morphine or other opioids produces potent antinociception at supraspinal sites and also activates the descending pain control pathways, which are mediated by the brainstem rostral ventromedial medulla (RVM) (Basbaum and Fields, 1984; Pavlovic and Bodnar, 1998; Smith et al., 1988). The RVM contains μ-, δ-, and κ-opioid receptors and it is a major locus for the descending control of nociception and opioid analgesia (Bowker and Dilts, 1988; Gutstein et al., 1998; Kalyuzhny and Wessendorf, 1998). Importantly, the tail-flick response is modulated in the RVM (Gilbert and Franklin, 2001). According to Sarton et al. (2001), ketamine interacts with the μopioid system and produces supraspinal antinociception (Sarton et al., 2001). It enhances opioid-induced analgesic signaling by modulating phosphorylation in cells that endogenously express μ-opioid receptors (Gupta et al., 2011). Additionally, ketamine-mediated spinal antinociception is antagonized by the opioid receptor antagonist naloxone, indicating that endogenous opioids might be involved (Crisp et al., 1991; Pekoe and Smith, 1982). Furthermore, ketamineinduced potentiation of morphine analgesia was completely abolished by naloxone (Campos et al., 2006). Likewise, our results demonstrated that naloxone inhibited central
ketamine-induced antinociception in a dose-dependent manner. This may be a direct effect on the μ opioid receptor or an indirect effect via release of endogenous opioid peptides that act on opioid receptors. Naloxone has been useful for receptor affinity determination of type-selective opioids in mammals; however, though it preferentially interacts with μ binding sites (KD ¼3.9 nM), it also has significant affinity for κ-opioid receptors (KD ¼ 16 nM) and a lesser affinity for δ-opioid receptors (KD ¼ 95 nM) (Satoh and Minami, 1995). To clarify which receptor subtype would be involved in ketamine-mediated central antinociception, highly selective antagonists were used, namely clocinnamox, naltrindole and nor-binaltorphimine. Clocinnamox is an irreversible μopioid receptor antagonist with apparent Ki values of 0.7, 1.9 and 5.7 nM for mouse μ, δ and κ receptors, respectively (Burke et al., 1994). Naltrindole has 223- and 346-fold greater activity for δ than for μ and κ opioid receptors (Portoghese et al., 1990), and nor-binaltorphimine is 27- to 29-fold less potent, respectively, for μ and δ binding sites compared with κ receptor binding sites (Rothman et al., 1988). The results demonstrated that clocinnamox and naltrindole, but not- nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner, suggesting the participation of μ and δ opioid receptors in this effect. Accordingly, the PAG has a high concentration of opioid receptors μ and δ (Yaksh et al., 1988). In contrast, it was demonstrated that the ketamine potentiate the antinociceptive effects of μ- but not δ- or κ-opioid agonists in a mouse model of acute pain (Baker et al., 2002). In order to add more data about the action of naloxone, clocinnamox and naltrindole in this work, bestatin, an aminopeptidase inhibitor that cleaves enkephalin at the tyrosylglycine bond (Hersh, 1982; Jia et al., 2010), was used. In vivo, enkephalins appear to be degraded by enzymes such as neutral endopeptidase and aminopeptidase (Roques et al., 1993). It was shown that intravenous injection of RB101, a dual inhibitor of enkephalinases, significantly reduced the total number of carrageenan-evoked c-Fos-immunoreactivity nuclei in the spinal cord and that this effect was blocked by mand κ-opioid receptor antagonists administration, suggesting that in enkephalin-induced antinociception, functional interactions between opioid receptors may occur (Le Guen et al., 2003). Other opioid peptides, such as β-endorphin or dynorphin, appear to be resistant to neutral endopeptidase and, to a lesser extent, aminopeptidase (Nieto et al., 2001). Our data demonstrated that bestatin administration increased low-dose (5 μg) ketamine-induced central antinociception, suggesting endogenous opioid peptide mobilization. Really, peptidases are capable of limiting the activation of μ-opioid receptors in the dorsal horn by physiologically released opioids and supports evidence that inhibitors of opioid-degrading peptidases have valuable analgesic properties (Roques, 2000). Additionally, pilot experiments performed by our group showed that clocinnamox and naltrindole prevent the enhanced ketamine antinociception by bestatin (data not shown). In conclusion, our results suggest that the central antinociceptive effect of ketamine is associated with endogenous opioid release that acts on μ and δ opioid receptors. The results of this work contribute to a greater understanding of the central antinociceptive mechanisms of a drug widely
Please cite this article as: Pacheco, D.d.F., et al., Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Research (2014), http://dx.doi.org/10.1016/j.brainres.2014.03.026
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used in veterinary therapy; however, more work needs to be done to elucidate the relationship between ketamine and endogenous opioids.
4.
Experimental procedures
4.1.
Animals
substance was assessed in pilot experiments and literature data (Romero et al., 2013). The nociceptive threshold was always measured in the mouse tail and the measurements of latency were performed at the following times: 0, 5, 10, 15 and 30 min.
4.5.
The experiments were performed on 25–30 g male Swiss mice (n¼ 5 per group) from the CEBIO (The Animal Centre) of the University of Minas Gerais (UFMG). The mice were housed in a temperature-controlled room (2371 1C) on an automatic 12-h light/dark cycle (06:00–18:00 h of light phase). All testing was carried out during the light phase (08:00–15:00 h). Food and water were freely available until the onset of the experiments. The algesimetric protocol was approved by the Ethics Committee on Animal Experimentation (CETEA) of UFMG.
4.2.
Algesimetric method
The tail-flick test used in the present study was conducted in accordance with the procedure described by D'Amour and Smith (1941) with a slight modification. Briefly, following restraining of the mouse by one of experimenter's hand, a heat source was applied 2 cm from the tip of the tail, and the time(s) required for the animal to withdraw its tail from the heat source was recorded as the tail-flick latency. The intensity of the heat was adjusted so that the baseline latencies were between 3 and 4 s. To avoid tissue damage, the cut-off time was established at 9 s. The baseline latency was obtained for each animal before drug administration (zero time) by calculating an average of three consecutive trials. To reduce stress, mice were habituated to the apparatus 1 day prior to conducting the experiments.
4.3.
Intracerebroventricular injection (i.c.v.)
Animals were constrained by a special device, which immobilizes their body, except for their head. With one hand the experimenter restrained the animal head and then injected the drugs into its right lateral ventricle, by intracerebroventricular route using a Hamilton syringe of 5 μl. The site of injection was 1 mm from either side of the midline on a line Q3 drawn through the anterior base of the ears (modified from Haley and Mccormick (1957)). The syringe was inserted perpendicularly through the skull into the brain in the profundity of 2 mm and 2 μl of solution was injected. For ascertaining the areas in the brain ventricular system into which the drugs penetrated, dilution of the drugs in Evans blue 0.5% was realized and the brain were sectioned for confirmation after experiments under anesthesia.
4.4.
Experimental protocol
All drugs were i.c.v. administered into the lateral ventricle. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine and bestatin were administered 1 min prior to the ketamine. The protocol to determine the best moment for the injection of each
5
Statistical analysis
Data were analyzed statistically by Repeated Measures ANOVA with post-hoc Bonferroni's test for multiple comparisons. Probabilities less than 5% (Po0.05) were considered to be statistically significant.
4.6.
Chemicals
The following drugs and chemicals were used: ketamine (Sigma, USA), opioid receptor antagonist naloxone (Sigma), μ opioid receptor antagonist clocinnamox (Tocris, USA), δ opioid receptor antagonist naltrindole (Tocris), κ-opioid receptor antagonist nor-binaltorphimine (Sigma) and aminopeptidase inhibitor bestatin (Sigma). All drugs were dissolved in saline and injected in a volume of 2 μl into the lateral ventricle. The saline used for dilution of all drugs contained a 0.5% of Evans Blue.
Conflicts of interest The authors state no conflict of interest.
Acknowledgments Fellowship by Conselho Nacional de Pesquisa (CNPq).
r e f e r e nc e s
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