5
REVIEW ARTICLE Activation of the Naloxone-sensitive Sigma Receptor by (þ)-Morphine or ()-Morphine Attenuates ()-Morphine-induced Analgesia and Addiction Leon F. Tseng * Professor Emeritus, Medical College of Wisconsin, Milwaukee, WI, USA article info Article history: Received: Aug 6, 2013 Revised: Aug 6, 2013 Accepted: Aug 6, 2013 KEY WORDS: addiction; antinociceptive tolerance; conditioned place preference; (þ)-morphine; ()-morphine; naloxone-sensitive sigma receptors ()-Morphine, but not (þ)-morphine, interacts with m-opioid receptors to produce antinociception (analgesia). The antinociception produced by ()-morphine is attenuated by pretreatment with (þ)-morphine or ()-morphine given spinally, supraspinally, or systemically. This phenomenon has been dened as antianalgesia, which is induced by (þ)-morphine or ()-morphine against the ()-morphine- induced antinociception following activation of the naloxone-sensitive s receptors. In addition, (þ)-morphine or ()-morphine pretreatment attenuates the antinociception produced by d-opioid re- ceptor agonist deltorphin II or k-opioid receptor agonist U50,488 H in m-opioid receptor knockout mice. The antianalgesia induced by (þ)-morphine or ()-morphine against ()-morphine-induced analgesia is mediated through activation of p38-mitogen-activated protein kinase. ()-Morphine, but not (þ)-morphine, induces the conditioned place preference, and the conditioned place preference induced by ()-morphine is attenuated by pretreatment with (þ)-morphine or ()-morphine. Furthermore, (þ)-morphine blocks the increase in the extracellular dopamine in the nucleus accumbens shell pro- duced by m-opioid agonist endomorphin-1 from the ventral tegmental area. These effects of (þ)-morphine in attenuating the ()-morphine-induced conditioned place preference and increased release of dopamine are also mediated through activating naloxone-sensitive s receptors. In conclusion, the review article depicts the mechanisms involved in the acute antinociceptive (analgesic) tolerance to ()-morphine and the attenuation of ()-morphine-induced conditioned place preference (addiction) with (þ)-morphine. Copyright Ó 2013, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved. 1. Introduction The naturally occurring morphine alkaloid, which is isolated from the juice of the opium poppy, Papaver somniferum, is stereo- chemically identied as a levorotatory form. ()-Morphine in- teracts with m-opioid receptors to produce potent antinociceptive, addictive, and other pharmacological effects. By contrast, the dextrorotatory (þ)-morphine, which is synthesized from sinome- nine, 1 does not have any afnity for m-opioid receptors and there- fore does not produce any m-opioid receptor-mediated pharmacological effects. 2 However, pretreatment with (þ)-morphine at an extremely low dose attenuates the anti- nociceptive effects produced by ()-morphine. Similarly, pre- treatment with ()-morphine at a dose much higher than that of (þ)-morphine also attenuates the ()-morphine-produced antinociception. 3e5 Place conditioning, a technique that measures the secondary reinforcing effects of drugs, has been used to assess the ()-morphine-induced motivational effects. ()-Morphine in- creases the conditioned place preference and the increase in the conditioned place preference produced by ()-morphine is atten- uated by (þ)-morphine pretreatment. 6,7 The stereoselective action of (þ)-morphine over ()-morphine in attenuating the ()-morphine-induced antinociception clearly in- dicates that the antianalgesic effect of (þ)-morphine and ()-morphine is not mediated by the blockade of the opioid re- ceptors. This is also demonstrated by the nding that the attenuation of the ()-morphine-induced antinociception induced by (þ)-morphine or ()-morphine is equally reversed by (þ)-naloxone and ()-naloxone and is also reversed by s receptor antagonist BD1047. 4,5 Other (þ)-opiates such as (þ)-pentazocine interact with s re- ceptors, which are distinct from classical opioid receptors. s Re- ceptors have been reported to play an important role in the modulation of analgesia produced by m-, d-, or k-opioid receptor agonists. 8-10 (þ)-Pentazocine antagonizes the ()-morphine- * Leon F. Tseng, 794 Lakeshore Drive, Redwood City, CA 94065, USA. E-mail: L. F. Tseng <[email protected]> Contents lists available at ScienceDirect Journal of Experimental and Clinical Medicine journal homepage: http://www.jecm-online.com 1878-3317/$ e see front matter Copyright Ó 2013, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.jecm.2013.08.002 J Exp Clin Med 2013;5(5):167e171

Activation of the Naloxone-sensitive Sigma Receptor by (+)-Morphine or (−)-Morphine Attenuates (−)-Morphine-induced Analgesia and Addiction

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lable at ScienceDirect

J Exp Clin Med 2013;5(5):167e171

Contents lists avai

Journal of Experimental and Clinical Medicine

journal homepage: http : / /www.jecm-onl ine.com

REVIEW ARTICLE

Activation of the Naloxone-sensitive Sigma Receptor by (þ)-Morphineor (�)-Morphine Attenuates (�)-Morphine-induced Analgesia andAddiction

Leon F. Tseng*

Professor Emeritus, Medical College of Wisconsin, Milwaukee, WI, USA

a r t i c l e i n f o

Article history:Received: Aug 6, 2013Revised: Aug 6, 2013Accepted: Aug 6, 2013

KEY WORDS:addiction;antinociceptive tolerance;conditioned place preference;(þ)-morphine;(�)-morphine;naloxone-sensitive sigma receptors

* Leon F. Tseng, 794 Lakeshore Drive, Redwood CityE-mail: L. F. Tseng <[email protected]>

1878-3317/$ e see front matter Copyright � 2013, Tahttp://dx.doi.org/10.1016/j.jecm.2013.08.002

(�)-Morphine, but not (þ)-morphine, interacts with m-opioid receptors to produce antinociception(analgesia). The antinociception produced by (�)-morphine is attenuated by pretreatment with(þ)-morphine or (�)-morphine given spinally, supraspinally, or systemically. This phenomenon has beendefined as antianalgesia, which is induced by (þ)-morphine or (�)-morphine against the (�)-morphine-induced antinociception following activation of the naloxone-sensitive s receptors. In addition,(þ)-morphine or (�)-morphine pretreatment attenuates the antinociception produced by d-opioid re-ceptor agonist deltorphin II or k-opioid receptor agonist U50,488 H in m-opioid receptor knockout mice.The antianalgesia induced by (þ)-morphine or (�)-morphine against (�)-morphine-induced analgesia ismediated through activation of p38-mitogen-activated protein kinase. (�)-Morphine, but not(þ)-morphine, induces the conditioned place preference, and the conditioned place preference inducedby (�)-morphine is attenuated by pretreatment with (þ)-morphine or (�)-morphine. Furthermore,(þ)-morphine blocks the increase in the extracellular dopamine in the nucleus accumbens shell pro-duced by m-opioid agonist endomorphin-1 from the ventral tegmental area. These effects of(þ)-morphine in attenuating the (�)-morphine-induced conditioned place preference and increasedrelease of dopamine are also mediated through activating naloxone-sensitive s receptors. In conclusion,the review article depicts the mechanisms involved in the acute antinociceptive (analgesic) tolerance to(�)-morphine and the attenuation of (�)-morphine-induced conditioned place preference (addiction)with (þ)-morphine.

Copyright � 2013, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved.

1. Introduction

The naturally occurring morphine alkaloid, which is isolated fromthe juice of the opium poppy, Papaver somniferum, is stereo-chemically identified as a levorotatory form. (�)-Morphine in-teracts with m-opioid receptors to produce potent antinociceptive,addictive, and other pharmacological effects. By contrast, thedextrorotatory (þ)-morphine, which is synthesized from sinome-nine,1 does not have any affinity for m-opioid receptors and there-fore does not produce any m-opioid receptor-mediatedpharmacological effects.2 However, pretreatment with(þ)-morphine at an extremely low dose attenuates the anti-nociceptive effects produced by (�)-morphine. Similarly, pre-treatment with (�)-morphine at a dose much higher than thatof (þ)-morphine also attenuates the (�)-morphine-produced

, CA 94065, USA.

ipei Medical University. Published

antinociception.3e5 Place conditioning, a technique that measuresthe secondary reinforcing effects of drugs, has been used to assessthe (�)-morphine-induced motivational effects. (�)-Morphine in-creases the conditioned place preference and the increase in theconditioned place preference produced by (�)-morphine is atten-uated by (þ)-morphine pretreatment.6,7

The stereoselective action of (þ)-morphine over (�)-morphine inattenuating the (�)-morphine-induced antinociception clearly in-dicates that the antianalgesic effect of (þ)-morphine and(�)-morphine is not mediated by the blockade of the opioid re-ceptors. This is also demonstrated by the finding that the attenuationof the (�)-morphine-induced antinociception induced by(þ)-morphine or (�)-morphine is equally reversed by (þ)-naloxoneand (�)-naloxone and is also reversed by s receptor antagonistBD1047.4,5

Other (þ)-opiates such as (þ)-pentazocine interact with s re-ceptors, which are distinct from classical opioid receptors. s Re-ceptors have been reported to play an important role in themodulation of analgesia produced by m-, d-, or k-opioid receptoragonists.8-10 (þ)-Pentazocine antagonizes the (�)-morphine-

by Elsevier Taiwan LLC. All rights reserved.

L.F. Tseng168

induced analgesia, which is reversed by s receptorantagonist haloperidol.11 Thus, pretreatment with (þ)-morphine,(�)-morphine, or (þ)-pentazocine all attenuates the anti-nociception produced by (�)-morphine and the attenuation of the(�)-morphine-induced antinociception induced by (þ)-morphine,(�)-morphine, or (þ)-pentazocine is reversed by (þ)-naloxone andby the s receptor antagonist BD1047.5,6,12 The findings indicatethat, like (þ)-pentazicine, (þ)-morphine and (�)-morphineattenuate the (�)-morphine-induced antinociception throughactivating the naloxone-sensitive s receptors, originally proposedby Martin et al13 in 1976 and later by Tsao and Su14 in 1997.

2. Attenuation of (L)-morphine-induced antinociception(analgesia) by (D)-morphine or (L)-morphin

2.1. Stereoselective action of (þ)-morphine over (�)-morphinegiven systemically in attenuating the antinociception produced by(�)-morphine given systemically in mice

The tail-flick test has been used to measure the antinociceptiveresponse to (�)-morphine.15 (�)-Morphine at a dose of 5 mg/kggiven subcutaneously produces the tail-flick inhibition in male CDmice. Pretreatment with (þ)-morphine at a pg/kg dose range(0.01e10 ng/kg, subcutaneously) or (�)-morphine at a higher mg/kgdose range (0.01e1 mg/kg) given subcutaneously for 60 minutesdose-dependently attenuates the (�)-morphine-induced tail-flickinhibition. The 50% effective dose (ED50) values for (þ)-morphineand (�)-morphine for attenuating the (�)-morphine-induced tail-flick inhibition are 30.6 pg/kg and 97.3 mg/kg, respectively. Thus,(þ)-morphine is about 3,000,000-fold more potent than(�)-morphine in attenuating the (�)-morphine-induced anti-nociception. Both that (þ)-morphine does not have any affinity form-opioid receptors, and that the extremely high stereoselectiveaction of (þ)-morphine over (�)-morphine in attenuating the(�)-morphine-induced antinociception clearly suggest that theantianalgesic effect of (þ)-morphine and (�)-morphine is notmediated by the blockade of the m-opioid receptors.6

2.2. Stereoselective action of (þ)-morphine over (�)-morphinegiven spinally or supraspinally in attenuating the (�)-morphine-induced antinociception

Both spinal and supraspinal sites are involved in the analgesiaproduced by (�)-morphine. The antianalgesic actions of(þ)-morphine and (�)-morphine given spinally against the anal-gesia produced by (�)-morphine given spinally has been studied inmale CD mice. Intrathecal pretreatment with (þ)-morphine with adose of 0.3e33 fmol or (�)-morphine at 0.009e0.3 nmol dose-dependently attenuates the tail-flick inhibition produced by intra-thecally administered (�)-morphine. The ED50 value for(þ)-morphine and (�)-morphine to produce the antianalgesia is1.07 fmol and 0.076 nmol, respectively. Thus, (þ)-morphine is71,000-fold more potent than (�)-morphine in producing anti-analgesia against (�)-morphine-induced analgesia, indicating thatthe extremely high stereoselective action of (þ)-morphine over(�)-morphine can produce antianalgesia in the mouse spinalcord.3,4

These studies have also been undertaken to determine if thesame phenomenon observed in the mouse spinal cord also takesplace in the supraspinal ventral periaqueductal gray of the rat.Pretreatment with (þ)-morphine for 45 minutes at 0.3e3.3 fmoldose-dependently attenuates the tail-flick inhibition produced by(�)-morphine (9 nmol) given into the ventral periaqueductal grayin CD-1 rats. Likewise, pretreatment with (�)-morphine for45 minutes at a higher dose (3e900 pmol) also dose-dependently

attenuates the tail-flick inhibition produced by (�)-morphine.Thus, (þ)-morphine is about 270,000-fold more potent than(�)-morphine in attenuating the (�)-morphine-induced tail-flickinhibition, indicating the extremely high stereoselective action of(þ)-morphine over (�)-morphine in attenuating the(�)-morphine-induced antinociception at the supraspinal sites.7

Thus, the antianalgesic effect of (þ)-morphine and (�)-morphineagainst the (�)-morphine-induced analgesia takes place both at thesupraspinal and spinal sites. These experiments described abovewith (�)-morphine also help to explain the mechanism involved inthe acute antinociceptive tolerance to (�)-morphine.

2.3. Naloxone-sensitive s receptors are involved in attenuation of(�)-morphine-induced antinociception by (þ)-morphine and(�)-morphine

A naloxone-sensitive, haloperidol-sensitive, [3H](þ)SKF-10047-binding protein has been purified from the rat brain membraneby affinity chromatography originally designed to purify s re-ceptors.14 [3H](þ)-SKF-10047 binding to the protein is inhibited by(þ)-pentazocine, (�)-pentazocine, (�)-morphine, (�)-naloxone,haloperidol, or (þ)-SKF-10047, but not the prototypic s receptorligand, such as 1.3-di-o-tolylguanidine, and progesterone. Thisreceptor is therefore tentatively defined as the naloxone-sensitives receptor, which resembles the opiate s receptor originallyproposed by Martin et al13 in 1976. (þ)-Naloxone, an enantiomer ofthe nonselective m-opioid receptor antagonist (�)-naloxone, hasbeen shown not to have any affinity for m-opioid receptors or blockm-opioid-mediated analgesia.16 (þ)-Naloxone and the s receptorantagonist BD1047 are used as receptor antagonists to determine ifthe antianalgesia induced by (þ)-morphine or (�)-morphine ismediated through activating the naloxone-sensitive s receptors.(þ)-Naloxone or (�)-naloxone, and the s receptor antagonistBD1047 can reverse the (þ)-morphine- and (�)-morphine-inducedantianalgesic effect in the spinal cord of male CD-1 mice.3,4 Thesefindings indicate that the antianalgesia induced by (þ)-morphineand (�)-morphine is mediated through activating naloxone-sensitive s receptors. The results of these experiments also sug-gest that the acute antinociceptive tolerance to (�)-morphine isthrough activating the naloxone-sensitive s receptors, and notthrough desensitizing m-opioid receptors pretreated with(�)-morphine.

2.4. Pretreatment with (þ)-morphine or (�)-morphine attenuatesthe antinociception produced by d-opioid receptor agonistdeltorphin II or k-opioid receptor agonist U50,488 H in m-opioidreceptor knockout mice

The use of the transgenic m-opioid receptor knockout mice is auseful experimental approach in opioid and pain research. Micethat lack the m-opioid receptor gene have been generated by dis-rupting exon 117 or exons 2 and 3.18 The antinociception producedby the m-opioid receptor agonist (�)-morphine or endomorphion-1is reduced in heterozygous m-opioid receptor knockout (þ/�) miceand is virtually abolished in homozygous m-opioid receptorknockout (�/�) mice.19 The genetic approach clearly demonstratesthat the pharmacological and biological actions of (�)-morphineand other m-opioid receptor agonists are mediated through acti-vating m-opioid receptors.

Those studies used m-opioid receptor knockout mice, in whichexon 1 of the m-opioid receptor gene has been deleted.17 Theanalgesic responses are measured with the tail-flick test.15 Intra-thecal injection of (�)-morphine (3.0 nmol) inhibits the tail-flickresponse only in the wild type (þ/þ) mice, and partially inhibitsthe response in the heterozygous (þ/�) mice, but not in the

Morphine attenuates opioid analgesia and addiction 169

homozygous m-opioid receptor knockout (�/�) mice. Intrathecaladministration of d-opioid receptor agonist deltorphin II(12.8 nmol) inhibits the tail-flick response in wild type (þ/þ),heterozygous (þ/�), and homozygous (�/�) m-opioid receptorknockout mice, and the inhibition of the tail-flick response pro-duced by deltorphin II is completely blocked by pretreatment with(�)-morphine (0.3 nmol) or (þ)-morphine (33 fmol). Similarly,intrathecal administration of k-opioid receptor agonist U50,488 H(123.2 nmol) inhibits the tail-flick response in wild type (þ/þ),heterozygous (þ/�), and homozygous (�/�) m-opioid receptorknockout mice, and the inhibition of the tail-flick response pro-duced by k-opioid receptor agonist U50,488 H is completelyblocked by pretreatment with (�)-morphine (0.3 nmol) or(þ)-morphine (33 fmol).20 As shown in Figure 1, (þ)-morphine and(�)-morphine can attenuate the antinociception produced by m-opioid receptor agonist (�)-morphine, d-opioid receptor agonistdeltorphin II, k-opioid receptor agonist, and U50,488 H.

2.5. p38 Mitogen-activated protein kinase inhibitor SB203580reverses antianalgesia induced by (þ)-morphine or (�)-morphine inmouse spinal cord

The p38 mitogen-activated protein kinase (MAPK) is involved inregulating numerous cellular responses.21 p38 MAPK responds toenvironmental stress and its pathway is crucial to inflammatorycytokine production and signaling.22 Activation of p38 MAPK in thespinal microglia contributes to the hyperalgesia and allodyniafollowing peripheral nerve injury,23e25 and the inflammation-induced spinal pain processing.26,27 Activation of p38 MAPK isrequired for m-opioid receptor endocytosis,28 and chronicmorphinetreatment increases p38 MAPK phosphorylation, which is associ-ated with the development of antinociceptive tolerance to(�)-morphine.29e31

The p38 MAPK inhibitor, SB203580, is used to determine if theactivation of p38 MAPK is involved in mediating the antianalgesiainduced by (þ)-morphine or (�)-morphine in male CD-1 mice.Mice are pretreated intrathecally with SB203580 (24.2 nmol)30minutes prior to intrathecal injection of (þ)-morphine (33 fmol).(�)-Morphine (3.0 nmol) is injected intrathecally 45 minutes after(þ)-morphine injection and the tail-flick response is measured15 minutes after (�)-morphine injection. SB203580 (24.2 nmol)completely reverses the attenuation of (�)-morphine-induced tail-flick inhibition induced by (þ)-morphine. Similarly, intrathecalpretreatment with SB203580 (24.2 nmol) completely reverses theattenuation of the (�)-morphine-induced tail-flick inhibition

Figure 1 A schematic diagram depicting the molecular pathway for the blockade ofopioid analgesia by low doses of (þ)-morphine or (�)-morphine.4,5,12,20,34 Systemic,spinal, or supraspinal administration of (�)-morphine, deltorphin II, or U50,488 Hstimulates opioid m-, d-, or k-receptors, respectively, to produce antinociception(analgesia) measured with the tail-flick test. The antinociception produced is blockedor attenuated by pretreatment with low doses of (þ)-morphine or higher doses of(�)-morphine via activation of the naloxone-sensitive receptor.

induced by (�)-morphine (0.3 nmol). Thus, inhibition of p38 MAPKin the spinal cord by intrathecal treatment with SB 203580 reversesthe attenuation of the (�)-morphine-induced antinociceptioninduced by (þ)-morphine or (�)-morphine. The finding indicatesthat activation of p38 MAPK in the spinal cord is involved ininducing the antianalgesia caused by (þ)-morphine or(�)-morphine. This finding also suggests that p38 MAPK may beinvolved in the acute antinociceptive tolerance to (�)-morphine.30

Cui et al31 in 2006 reported that repeated intrathecal pretreatmentwith SB203580 attenuates the antinociceptive tolerance to(�)-morphine, assessed with the tail-flick test, indicating thatactivating p38 MAPK in the spinal cord plays an important role inthe development of tolerance to (�)-morphine analgesia.

To date, four different p38 isoforms, a, b, g, and d, have beenidentified.23 However, there are two p38 isoforms, a and b, found inthe spinal cord. Svensson et al27 in 2005 demonstrated that theisoforms are distinctly expressed in the spinal dorsal horn: p38a inthe neurons and p38 b in the microglia. SB203580 nonselectivelyinhibits both glial and neuronal p38 MAPK,32 thus, it is not clearthat (þ)-morphine and (�)-morphine act on glial or neuronal p38MAPK to produce antianalgesia. However, Wu et al4 in 2005demonstrated that pretreatment with the glial modulator pro-pentofylline reverses the antianalgesia induced by (þ)-morphine or(�)-morphine, suggesting that (þ)-morphine or (�)-morphine actson glia rather than neurons to induce antianalgesia. Others alsohave reported that p38 MAP kinase is activated in the spinalmicroglia after sciatic nerve ligation of hyperalgesia and allody-nia.23e26,33

3. Attenuation of (L)-morphine-induced conditional placepreference by (D)-morphine pretreatment

3.1. (�)-Morphine and other m-opioids induce conditioned placepreference

Place conditioning, which is a technique to measure the secondaryreinforcing effects of drugs effects, is used to assess morphine-induced motivational effects. In this procedure, the association thatdevelops between the presentation of a drug and a previouslyneutral stimulus, for example, different colored compartments of ashuttle box, is evaluated.7,34 The results obtained with this para-digm for rewarding drugs done by others are largely identical tothose obtainedwith the self-administrationparadigm technique forstudying addiction.35,36 m-Opioid agonists such as (�)-morphine,D-Ala2-N-MePhe4-Gly5-ol-enkephalin, or endomorphin-1 givensystemically or intracerebroventricularly in mice or rats produceconditioned place preference.37e41 The conditioned place prefer-ence produced by (�)-morphine is blocked by m-opioid receptorantagonist naltrexone or naloxonazine, indicating that this effect ismediated through stimulating m-opioid receptors.38,42

3.2. (�)-Morphine, but not (þ)-morphine, induces conditionedplace preference

Place conditioning is used to assess the motivational effect of(�)-morphine or (þ)-morphine in male CD rats.6,7 (�)-Morphinesulfate at a dose of 1e5 mg/kg given subcutaneously dose-dependently increases the conditioned place preference, whereas(þ)-morphine at a dose of 3 mg/kg given systemically does notinduce the conditioned place preference, nor does it induceconditioned place aversion.6 Earlier, Mucha and Herz43 in 1986found that (þ)-morphine even at a high dose (4 mg/kg) givensystemically does not induce any conditioned place preference orconditioned place aversion. (�)-Morphine at the same dose, how-ever, does induce conditioned place preference. Thus, the

Figure 2 A schematic diagram depicting the molecular pathway for the blockade of(�)-morphine-induced conditioned place preference by low doses of (þ)-morphine.6,7

(�)-Morphine given systemically or into the posterior nucleus accumbens shellstimulates the m-opioid receptors, and subsequently increases the release of dopaminein the posterior nucleus accumbens shell to induce the conditioned place preference(addiction). The conditioned place preference produced by (�)-morphine is blocked orinhibited by a low dose of (þ)-morphine via activation of the naloxone-sensitive sreceptors to inhibit the release of dopamine in the posterior nucleus accumbens shell.

L.F. Tseng170

conditioned place preference produced by (�)-morphine is ste-reospecific; it is only induced by the m-opioid receptor active iso-mers, such as levorotatory (�)-morphine, but not dextrorotatory(þ)-morphine.

3.3. (þ)-Morphine attenuates (�)-morphine-induced conditionedplace preference

(�)-Morphine sulfate (1e10 mg/kg) given intraperitoneally dose-dependently induces conditioned place preference. Pretreatmentwith (þ)-morphine at a dose from 0.1 mg/kg to 3 mg/kg given sub-cutaneously dose-dependently attenuates the conditioned placepreference induced by 5 mg/kg (�)-morphine. However,(þ)-morphine at a higher dose of 100 mg/kg does not affect the(�)-morphine-induced conditioned place preference. Thus,(þ)-morphine pretreatment induces a U-shaped doseeresponsecurve for attenuating the (�)-morphine-induced conditioned placepreference. Attenuation of the (�)-morphine-induced conditionedplace preference is reversed by pretreatment with the s receptorantagonist BD1047 {N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide}, indicating that(þ)-morphine attenuates the (�)-morphine-induced conditionedplace preference through activating s receptors.6

The ventral tegmental area and nucleus accumbens representtwo key structures of the mesolimbic dopaminergic system of thecentral nervous system for reinforcing properties of opiates.44,45

(�)-Morphine (2.5e10 mg) microinjected into the posterior nu-cleus accumbens shell dose-dependently induces conditionedplace preference. Pretreatment with (þ)-morphine at 0.1e10 pg,injected into the posterior nucleus accumbens shell for 45 minutes,dose-dependently attenuates the conditioned place preferenceinduced by (�)-morphine (5 mg) injected into the same posteriornucleus accumbens shell. However, (þ)-morphine at 0.1 ng and1 ng is less effective in attenuating the (�)-morphine-inducedconditioned place preference. Thus, as with systemic administra-tion, (þ)-morphine in the posterior nucleus accumbens shell alsoinduces a U-shaped doseeresponse curve for attenuating the(�)-morphine-induced conditioned place preference.7 Thus,(þ)-morphine can be used for the treatment of opiate addiction.The therapeutic window of the dose of (þ)-morphine for anti-addiction therapy should be in the picogram dose range. Higherdoses of (þ)-morphine are not effective in providing the thera-peutic effect.

3.4. (þ)-Morphine attenuates the increase in extracellulardopamine in the nucleus accumbens shell induced by m-opioidagonist endomorphin-1 from the ventral tegmental area

The specific m-opioid receptor agonist endomorphin-1, injected intothe ventral tegmental area, increases extracellular dopamine in theposterior nucleus accumbens shell. This increase in extracellulardopamine is blocked by (�)-naloxone pretreatment, indicating thatthe effect is mediated through activating the m-opioid receptor.Thus, stimulation of m-opioid receptors by (�)-morphine or otherm-opioids in the ventral tegmental area enhances mesolimbicdopaminergic neurotransmission, presumably through inhibitingGABAergic interneurons, resulting in disinhibiting mesolimbicdopaminergic neurons and increasing both somatodendritic andaxonal dopamine release.46e51An increase in the extracellulardopamine in the nucleus accumbens has been reported by systemic(�)-morphine and intracerebroventricular injection of the m-re-ceptor agonist, [D-Ala2-N-MePhe4-Gly-ol5]enkephalin.46,48 Theincreased release of dopamine in the posterior nucleus accumbensinduced by the m-opioid receptor agonist endomorphin-1 isblocked by (þ)-morphine injected into the ventral tegmental area.7

Thus, the behavioral response to (þ)-morphine in attenuating the(�)-morphine-induced conditioned place preference is correlatedwith the biochemical finding that (þ)-morphine blocks the in-crease in extracellular dopamine in the posterior nucleus accum-bens elicited by the specific m-opioid receptor agonistendomorphin-1 from the ventral tegmental area. The finding sup-ports the hypothesis that (þ)-morphine, which activates naloxone-sensitive s receptors, inhibits the (�)-morphine-induced condi-tioned place preference by attenuating the increase in extracellulardopamine in the mesolimbic ventral tegmental areaenucleusaccumbens system. Figure 2 is a schematic diagram of the anti-addiction effect of (þ)-morphine.

References

1. Iijima I, Minamikawa J-I, Jacobsen AE, Brossi A, Rice KE. Studies in the(þ)-morphinan series-4. A markedly improved synthesis of (þ)-morphine.J Org Chem 1978;43:1462e3.

2. Jacquet YF, Klee WA, Rice KC, Iijima I, Minamikawa J. Stereospecific and non-stereospecific effects of (þ)- and (�)-morphine: evidence for a new class ofreceptors. Science 1977;198:842e5.

3. Wu HE, Thompson J, Sun HS, Leitermann RJ, Fujimoto JM, Tseng LF. Non-opioidergic mechanism mediating morphine-induced antianalgesia in themouse spinal cord. J Pharmacol Exp Ther 2004;310:240e6.

4. Wu HE, Thompson J, Sun HS, Terashvili M, Tseng LF. Antianalgesia: stereo-selective action of dextro-morphine over levo-morphine on glia in the mousespinal cord. J Pharmacol Exp Ther 2005;314:1101e8.

5. Terashvili M, Wu HE, Moore RM, Harder DR, Tseng LF. (þ)-Morphine and(�)-morphine stereoselectively attenuate the (�)-morphine-produced tail-flickinhibition via the naloxone-sensitive sigma receptor in the ventral peri-aqueductal gray of the rat. Eur J Pharmacol 2007;571:1e7.

6. Wu HE, Schwasinger ET, Terashivili M, Tseng LF. dextro-Morphine attenuatesthe morphine-produced conditioned place preference via the sigma1 receptoractivation in the rat. Eur J Pharmacol 2007;562:221e6.

7. Terashvili M, Wu HE, Schwasinger ET, Hung KC, Hong JS, Tseng LF.(þ)-Morphine attenuates the (�)-morphine-produced conditioned place pref-erence and the m-opioid receptor-mediated dopamine increase in the poste-rior nucleus accumbens of the rat. Eur J Pharmacol 2008;587:147e54.

8. Mei J, Pasternak GW. s1 Receptor modulation of opioid analgesia in the mouse.J Pharamcol Exp Ther 2002;300:1070e4.

9. Marrazzo A, Parenti C, Scavo V, Ronsisvalle S, Scoto GM, Ronsisvalle G. In vivoevaluation of (þ)-MR200 as a selective sigma ligand modulating MOP, DOP andKOP supraspinal analgesia. Life Sci 2006;78:2449e53.

10. Chien CC, Pasternak GW. Selective antagonism of opioid analgesia by a sigmasystem. J Pharmacol Exp Ther 1994;271:1583e90.

Morphine attenuates opioid analgesia and addiction 171

11. Chien CC, Pasternak GW. Functional antagonism of morphine analgesia by(þ)-pentazocine: evidence for an anti-opioid sigma 1 system. Eur J Pharmacol1993;250:R7e8.

12. Tseng LF, Hogan QH, Wu HE. (þ)-Morphine attenuates the (�)-morphine-produced tail-flick inhibition via the sigma-1 receptor in the mouse spinalcord. Life Sci 2011;89:875e7.

13. Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects ofmorphine and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 1976;197:517e32.

14. Tsao L-I, Su TP. Naloxone-sensitive, haloperidol-sensitive, [3H](þ)SKF-10047-binding protein partially purified from rat liver and rat brain membranes: anopioid/sigma receptor? Synapse 1997;25:117e24.

15. D’Amour EF, Smith DL. A method for determining loss of pain sensation.J Pharmacol Exp Ther 1941;72:74e9.

16. Iijima I, Minamikawa J-I, Jacobsen AE, Brossi A, Rice KE. Studies in the(þ)-morphine series-5: synthesis and biological properties of (þ)-naloxone.J Med Chem 1978;21:398e400.

17. Sora I, Takahashi N, Funada M, Ujika H, Ravay RS, Donovan DM, et al. Opiate re-ceptor knockoutmice definem-receptor role in endogenous nociceptive responseand morphine-induced analgesia. Proc Natl. Acad Sci U S A 1997;94:1544e9.

18. Loh HH, Liu HS, Cavalli A, Yang W, Chen YE, Mei LN. m-Opioid receptorknockout in mice: effects on ligand-induced analgesia and morphine lethality.Mol Brain Res 1998;54:321e6.

19. Mizoguchi H, Narita M, Oji DE, Suganuma C, Nagase H, Sora I, Uhl GR, et al.m-Opioid receptor gene-dose dependent reductions in G-protein activation inthe pons/medulla and antinociception induced by endomorphins in m-opioidreceptor knockout mice. Neuroscience 1999;94:203e7.

20. Wu HE, Sun HS, Terashivili M, Schwasinger E, Sora I, Hall FS, Uhl GR, et al.dextro-Morphine and levo-morphine induce antianalgesia against anti-nociception produced by opioid d- and k-agonists in m-opioid receptorknockout mice. Eur J Pharmacol. 2006;531:103e7.

21. Nebreda A, Porras A. p38 MAPK kinase: beyond the stress response. TrendsBiochem Sci 2000;25:257e60.

22. Kumar S, Boehm J, Lee JC. P38 MAP kinases: key signaling molecules as ther-apeutic targets for inflammatory diseases. Nat Rev Drug Discov 2003;2:717e26.

23. Jin SX, Zhuang AY, Woolf CJ, Ji RR. p38 Mitogen-activated protein kinase isactivated after a spinal nerve ligation in the spinal cord microglia and dorsalroot ganglion neurons and contributes to the generation of neuropathic pain.J Neurosci 2003;23:4017e22.

24. Schafer M, Svensson CI, Sommer C, Sorkin LS. Tumor necrosis factor-a inducesmechanical allodynia after spinal nerve ligation by activation of p38 MAPK inprimary sensory neurons. J Neurosci 2003;23:2517e21.

25. Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K. Activation ofp38 mitogen-activated protein kinase in spinal hyperactive microglia con-tributes to pain hypersensitivity following peripheral nerve injury. Glia2004;45:89e95.

26. Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM,Freshwater JD, Catalano R, et al. Activation of p38 mitogen-activated proteinkinase in spinal microglia is a critical link in inflammation-induced spinal painprocessing. J Neurochem 2003;86:1534e44.

27. Svensson CI, Fitzsimmons B, Azizi S, Powell HC, Hua XY, Yaksh TL. Spinal p38bisoform mediates tissue injury-induced hyperalgesia and spinal sensitization.J Neurochem 2005;92:108e20.

28. Mace G, Miaczynska M, Zerial M, Nebreda AR. Phosphorylation of EEA1 by p38MAP kinase regulates m-opioid receptor endocytosis. EMBO J 2005;24:3235e46.

29. Ma W, Zheng WH, Powell K, Jhamandas K, Quirion R. Chronic morphineexposure increases the phosphorylation of MAP kinases and the transcriptionfactor CREB in dorsal root ganglion neurons: an in vitro and in vivo study. Eur JNeurosci 2001;14:1091e104.

30. Wu HE, Sun HS, Cheng CW, Tseng LF. p38 Mitogen-activated protein kinaseinhibitor SB203580 reverses the antianalgesia induced by dextro-morphine ormorphine in the mouse spinal cord. Eur J Pharmacol 2006;550:91e4.

31. Cui Y, Chen Y, Zhi JL, Guo RX, Feng JQ, Chen PX. Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine anti-nociceptive tolerance. Brain Res 2006;1069:235e43.

32. Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S, Badger AM, et al. In-hibition of p38 mitogen-activated protein kinase provides neuroprotection incerebral focal ischemia. Med Res Rev 2001;21:129e45.

33. Ji RR, Babu K, Brenner GJ, Woold CJ. ERK MAP kinase activation in superficialspinal cord neurons induces prodynorphin and NK-1 upregulation and con-tributes to persistent inflammatory pain hypersensitivity. J Neurosci 2002;22:478e85.

34. Wu HE, Hong JS, Tseng LF. Stereoselective action of (þ)-morphine over(�)-morphine in attenuating the (�)-morphine-produced antinociception viathe naloxone-sensitive sigma receptor in the mouse. Eur J Pharmacol 2007;571:145e51.

35. Spyraki C. Drug reward studied by use of place conditioning in rats. In:Lades M, editor. The psychopharmacology of addiction. Oxford: Oxford Univer-sity Press; 1988. p. 97e114.

36. Carr CD, Fibinger HC, Phillips AG. Conditioning place preference as ameasure of drug reward. In: Liebman JM, Cooper SJ, editors. The neuro-pharmacological basis of reward. Oxford: Sciences Publication Press; 1989.p. 264e319.

37. Neisewander JL, Pierce RC, Bardo MT. Naloxone enhances the expression ofmorphine-induced conditioned place preference. Psychopharmacol 1990;100:201e5.

38. Piepponen TP, Kivastik T, Katajamaki J, Zharkovsky A, Ahtee L. Involvement ofopioid mu 1 receptors in morphine-induced conditioned place preference inrats. Pharmacol Biochem Behav 1997;58:275e9.

39. Suzuki T, Funada M, Narita M, Misawa M, Nagase H. Pertussis toxin abolishesmu- and delta-opioid agonist-induced place preference. Eur J Pharmacol1991;205:85e8.

40. Terashvili M, Wu H, Leitermann RJ, Hung K, Clithero AD, Schwasinger ET,et al. Differential conditioned place preference responses to endomorphin-1and endomorphin-2 microinjected into posterior nucleus accumbensshell and ventral tegmental area in the rat. J Pharmacol Exp Ther 2004;309:816e24.

41. Wu H, MacDougall RS, Clithe AD, Terashvili M, Tseng LF. Opposite conditionedplace preference responses to endomorphin-1 and endomorphin-2 in themouse. Nuerosci Lett 2004;356:157e61.

42. Olmstead MC, Burns LH. Ultra-low-dose naltrexone suppresses rewarding ef-fects of opiates and aversive effects of opiate withdrawal in rats. Psycho-pharmacol 2005;12:1e6.

43. Mucha RF, Herz A. Preference conditioning produced by opioid activeand inactive isomers of levophanol and morphine in rat. Life Sci 1986;38:241e9.

44. Watson SJ, Trujillo KA, Herman JP, Akil H. Neuroanatomical and neurochemicalsubtrates of drug-seeking behavior: overview and future directions. In:Goldstein A, editor. Molecular and cellular aspects of the drug addiction. NewYork: Springer; 1989. p. 29e91.

45. Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol 1989;40:191e225.

46. Stinus L, Koob GF, Ling N, Bloom FE, Moal ML. Locomotor activation induced byinfusion of endorphin into the ventral tegmental area: evidence for opiate-dopamine interactions. Proc Natl Acad Sci U S A 1980;77:2323e7.

47. Kalivas PW, Duffy P. Effects of acute and daily neurotensin and enkephalintreatment on extracellular dopamine in the nucleus accumbens. J Neurosci1990;10:2940e9.

48. Spanagel R, Herz A, Shippenberg TS. The effects of opioid peptides on dopa-mine release in the nucleus accumbens: an in-vivo microdialysis study.J Neurochem 1990;55:1734e40.

49. Johnson SW, North RA. Opioids excite dopamine neurons by hyperpolarizationof local interneurons. J Neurosci 1992;12:483e8.

50. Klitenick MA, DeWitte P, Kalivas PW. Regulation of somatodendritic dopaminerelease in the ventral tegmental area by opioids and GABA: an in vivo micro-dialysis study. J Neurosci 1992;12:2623e32.

51. Devine DP, Leone P, Pocock D, Wise RA. Differential involvement of ventraltegmental mu, delta and kappa opioid receptors in modulation of basal mes-olimbic dopamine release: in vivo microdialysis studies. J Pharmacol Exp Ther1993;266:1236e46.