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Mechanism of opioid dependence and interaction between opioid receptors
European Journal of Pain (2001) 5 (Suppl. A): 63±65 doi:10.1053/eujp.2001.0282, available online at http://www.idealibrary.com on
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Mechanism of opioid dependence and interaction between opioid receptors Tsutomu Suzuki, Yayoi Kishimoto, Satoru Ozaki and Minoru Narita Department of Toxicology, School of Pharmacy, Hoshi University, Tokyo, Japan
Clinical studies have demonstrated that when opiates are used to control cancer pain, psychological dependence and analgesic tolerance are not a major concern. The present study was, therefore, designed to investigate the modulation of rewarding effects of opiates under inflammatory chronic pain. Formalin or carrageenan was injected into the plantar surface of the rat paw. Formalin and carrageenan reduced the paw pressure threshold. The hyperalgesia lasted for 9±13 days. The rewarding effect of morphine was evaluated by conditioned place preference paradigm. Morphine produced a significant place preference. This effect was significantly attenuated in inflamed groups compared with the respective non-inflamed groups. Furthermore, the morphine-induced place preference in the inflamed group gradually recovered to the respective control level as the inflammation healed. We also found that -receptor agonists markedly inhibited the rewarding effect of -receptor agonists. Therefore, to elucidate the mechanism of this attenuation, the effects of pretreatment with - and -receptor antagonists, nor-binaltorphimine (nor-BNI) and naltrindole (NTI), on the development of the morphine-induced place preference under inflammation were examined. Nor-BNI, but not NTI, eliminated the suppression of the morphine-induced place preference in inflamed groups. The morphine-induced increase in dopamine (DA) turnover in the limbic forebrain was suppressed under inflammation, and the suppression was abolished by the pretreatment with nor-BNI. These results suggest that endogenous -opioid systems may be activated by chronic inflammatory nociception, and then the activation of -opioid system may inhibit DA release in nucleus accumbens, resulting in the suppression of the development of rewarding effects produced by morphine. # 2001 European Federation of Chapters of the International Association for the Study of Pain KEYWORDS: opioid receptors, opioid dependence, chronic inflammatory nociception.
INTRODUCTION The World Health Organization published Cancer Pain Relief (WHO, 1996). This publication proposed a method for relief of cancer pain, based on a small number of relatively inexpensive drugs, including morphine. This method has been used worldwide. Undue anxiety about psychological dependence on morphine in cancer patients, has caused physicians and patients to use inadequate doses of opioids. Wide clinical experience has shown that psychological dependence does not occur in cancer patients as a result of receiving opioids for relief of pain. Correspondence to: Tsutomu Suzuki, PhD, Department of Toxicology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. E-mail: [email protected]
Physicians have endeavoured to use morphine for cancer pain relief without addiction. On the other hand, investigators in basic research have focused on the mechanisms of opiate tolerance and dependence. The present study was, therefore, designed to examine the modification of psychological dependence on and anti-nociceptive tolerance to morphine under chronic pain.
METHODS The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals, Hoshi University, as adopted by the Committee on Animal Research of Hoshi University, which is accredited by the Ministry of Education, Science, Sports and Culture of Japan.
1090-3801/010A0063 + 03 $35.00/0 & 2001 European Federation of Chapters of the International Association for the Study of Pain
64
T. SUZUKI
ET AL .
Animals
DA turnover
Male Sprague-Dawley rats were obtained from Tokyo Experimental Animals Inc. The animals were housed at a temperature of 22 1 C with a 12-h light-dark cycle (light on 8:30 am). Food and water were available ad libitum.
The brain was quickly removed and the limbic forebrain (including the nucleus accumbens) was dissected. The samples prepared according to the general method were injected onto the HPLC-ECD and the concentrations of DA, DOPAC and HVA were estimated. The DA turnover was calculated according to the following formula: DA turnover [DOPAC HVA/DA (ng/g of tissue)].
Inflammation model Formalin (2.5%, 50 ml) or carrageenan (1%, 100 ml) was injected into plantar surface of the rat paw. The pain threshold was evaluated according to the paw pressure method.
Place conditioning Place conditioning was started at the first day after formalin, carrageenan or vehicle injection. The apparatus consisted of a shuttlebox, which was divided into two compartments of equal size. One compartment was white with a textured floor and the other was black with a smooth floor. For conditioning, rats were confined to one compartment after drug injection and to the other compartment after saline injection for 50 min. The orders of the injection and the compartment were counterbalanced across the subjects. Conditioning sessions (two for drug: two for saline) were conducted once-daily. On day 5, conditioning was tested as follows: a neutral platform was inserted along the seam separating the compartments. The time spent in each compartment during a 900-second session was then measured automatically by an infrared beam sensor. Morphine (2±8 mg/kg) and saline (1.0 ml/kg) were injected i.p. on alternate days. In a combination study, rats were injected with NTI (3 mg/kg, i.p.) and nor-BNI (5 mg/kg, s.c.) 45 min and 6 h before treatment with morphine, respectively. The rats were immediately confined to the respective compartment after the injection. After conditioning, the tests were performed and the time spent in each compartment was measured. Conditioning scores represented the time spent in the drug-paired place minus the time spent in the saline-paired place.
European Journal of Pain (2001), 5 (Suppl. A)
RESULTS The formalin- and carrageenan-treated paws continued to swell for 11 and 15 days, and the decreases in these paw pressure thresholds lasted for 9 and 13 days, respectively. Therefore, in the present study, we performed the following experiments during the reduction in the paw pressure threshold. Morphine at 8 mg/kg produced a significant antinociceptive effect. This effect was gradually decreased by repeated injection of morphine in the non-inflamed group. However, in the inflamed group, the antinociceptive tolerance to morphine was significantly inhibited. In the non-inflamed group, morphine produced a dose-related place preference. A significant conditioning was observed at morphine doses of 4 and 8 mg/kg. Under these conditions, the morphineinduced place preference was significantly suppressed in inflamed groups compared with the non-inflamed group. The morphine-induced place preference in the inflamed group gradually recovered to the level of the non-inflamed group as the inflammation healed. Rats, with conditioning on the 14th day after the induction of inflammation showed a significant place preference by morphine, like non-inflamed rats. In the non-inflamed group, pretreatment with NTI, but not nor-BNI, significantly suppressed the morphine-induced place preference. By contrast, the attenuation of morphine-induced place preference in the inflamed group was reversed by the pretreatment with nor-BNI, but not NTI. Morphine at 8 mg/kg produced increases in DA turnover in the limbic forebrain of non-inflamed group. Under inflammatory nociception the increases
O PIOID
65
DEPENDENCE AND INTERACTION
in DA turnover in the limbic forebrain by morphine were significantly suppressed, and this suppression was reversed by the pretreatment with nor-BNI.
DISCUSSION In the present study, we found that inflammatory nociception produced by formalin and carrageenan inhibited the development of antinociceptive tolerance to morphine. As well as tolerance, the morphine-induced rewarding effect was significantly suppressed under chronic pain. Our findings are similar to the results of clinical experience in the use of morphine for relief of cancer pain (WHO, 1996). We also found that the suppression of the morphine-induced rewarding effect corresponds to the intensity of inflammatory nociception. It should be noted that the attenuation of morphine-induced place preference under inflammation was reversed by the pretreatment with -receptor antagonist but not -receptor antagonist. These results suggest that the activation of endogenous -opioid systems produced by the inflammatory nociception may contribute to the attenuation
of place preference induced by morphine in the presence of inflammatory nociception. It is well known that psychological dependence on morphine may be produced by the activation of mesolimbic DA system and this activation can be blocked by -receptor agonist (Funada et al., 1993). In the present study, we found that the increases in DA turnover in the limbic forebrain by morphine were significantly suppressed under inflammatory nociception, and the suppression was reversed by the pretreatment with -receptor antagonist. These results suggest that the attenuation of rewarding effect induced by morphine in the presence of inflammatory nociception may result from the inhibition of mesolimbic DA system by activated endogenous -opioid systems under inflammatory nociception.
REFERENCES Funada M, Suzuki T, Narita M, Misawa M, Nagase H. Blockade of morphine reward through the activation of -opioid receptors in mice. Neuropharmacology 1993; 32: 1315±1323. World Health Organization. Cancer Pain Relief. Geneva: World Health Organization, 1996: 14±37.
European Journal of Pain (2001), 5 (Suppl. A)
1
Mechanism of opioid dependence and interaction between opioid receptors Tsutomu Suzuki, Yayoi Kishimoto, Satoru Ozaki and Minoru Narita Department of Toxicology, School of Pharmacy, Hoshi University, Tokyo, Japan
Clinical studies have demonstrated that when opiates are used to control cancer pain, psychological dependence and analgesic tolerance are not a major concern. The present study was, therefore, designed to investigate the modulation of rewarding effects of opiates under inflammatory chronic pain. Formalin or carrageenan was injected into the plantar surface of the rat paw. Formalin and carrageenan reduced the paw pressure threshold. The hyperalgesia lasted for 9±13 days. The rewarding effect of morphine was evaluated by conditioned place preference paradigm. Morphine produced a significant place preference. This effect was significantly attenuated in inflamed groups compared with the respective non-inflamed groups. Furthermore, the morphine-induced place preference in the inflamed group gradually recovered to the respective control level as the inflammation healed. We also found that -receptor agonists markedly inhibited the rewarding effect of -receptor agonists. Therefore, to elucidate the mechanism of this attenuation, the effects of pretreatment with - and -receptor antagonists, nor-binaltorphimine (nor-BNI) and naltrindole (NTI), on the development of the morphine-induced place preference under inflammation were examined. Nor-BNI, but not NTI, eliminated the suppression of the morphine-induced place preference in inflamed groups. The morphine-induced increase in dopamine (DA) turnover in the limbic forebrain was suppressed under inflammation, and the suppression was abolished by the pretreatment with nor-BNI. These results suggest that endogenous -opioid systems may be activated by chronic inflammatory nociception, and then the activation of -opioid system may inhibit DA release in nucleus accumbens, resulting in the suppression of the development of rewarding effects produced by morphine. # 2001 European Federation of Chapters of the International Association for the Study of Pain KEYWORDS: opioid receptors, opioid dependence, chronic inflammatory nociception.
INTRODUCTION The World Health Organization published Cancer Pain Relief (WHO, 1996). This publication proposed a method for relief of cancer pain, based on a small number of relatively inexpensive drugs, including morphine. This method has been used worldwide. Undue anxiety about psychological dependence on morphine in cancer patients, has caused physicians and patients to use inadequate doses of opioids. Wide clinical experience has shown that psychological dependence does not occur in cancer patients as a result of receiving opioids for relief of pain. Correspondence to: Tsutomu Suzuki, PhD, Department of Toxicology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. E-mail: [email protected]
Physicians have endeavoured to use morphine for cancer pain relief without addiction. On the other hand, investigators in basic research have focused on the mechanisms of opiate tolerance and dependence. The present study was, therefore, designed to examine the modification of psychological dependence on and anti-nociceptive tolerance to morphine under chronic pain.
METHODS The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals, Hoshi University, as adopted by the Committee on Animal Research of Hoshi University, which is accredited by the Ministry of Education, Science, Sports and Culture of Japan.
1090-3801/010A0063 + 03 $35.00/0 & 2001 European Federation of Chapters of the International Association for the Study of Pain
64
T. SUZUKI
ET AL .
Animals
DA turnover
Male Sprague-Dawley rats were obtained from Tokyo Experimental Animals Inc. The animals were housed at a temperature of 22 1 C with a 12-h light-dark cycle (light on 8:30 am). Food and water were available ad libitum.
The brain was quickly removed and the limbic forebrain (including the nucleus accumbens) was dissected. The samples prepared according to the general method were injected onto the HPLC-ECD and the concentrations of DA, DOPAC and HVA were estimated. The DA turnover was calculated according to the following formula: DA turnover [DOPAC HVA/DA (ng/g of tissue)].
Inflammation model Formalin (2.5%, 50 ml) or carrageenan (1%, 100 ml) was injected into plantar surface of the rat paw. The pain threshold was evaluated according to the paw pressure method.
Place conditioning Place conditioning was started at the first day after formalin, carrageenan or vehicle injection. The apparatus consisted of a shuttlebox, which was divided into two compartments of equal size. One compartment was white with a textured floor and the other was black with a smooth floor. For conditioning, rats were confined to one compartment after drug injection and to the other compartment after saline injection for 50 min. The orders of the injection and the compartment were counterbalanced across the subjects. Conditioning sessions (two for drug: two for saline) were conducted once-daily. On day 5, conditioning was tested as follows: a neutral platform was inserted along the seam separating the compartments. The time spent in each compartment during a 900-second session was then measured automatically by an infrared beam sensor. Morphine (2±8 mg/kg) and saline (1.0 ml/kg) were injected i.p. on alternate days. In a combination study, rats were injected with NTI (3 mg/kg, i.p.) and nor-BNI (5 mg/kg, s.c.) 45 min and 6 h before treatment with morphine, respectively. The rats were immediately confined to the respective compartment after the injection. After conditioning, the tests were performed and the time spent in each compartment was measured. Conditioning scores represented the time spent in the drug-paired place minus the time spent in the saline-paired place.
European Journal of Pain (2001), 5 (Suppl. A)
RESULTS The formalin- and carrageenan-treated paws continued to swell for 11 and 15 days, and the decreases in these paw pressure thresholds lasted for 9 and 13 days, respectively. Therefore, in the present study, we performed the following experiments during the reduction in the paw pressure threshold. Morphine at 8 mg/kg produced a significant antinociceptive effect. This effect was gradually decreased by repeated injection of morphine in the non-inflamed group. However, in the inflamed group, the antinociceptive tolerance to morphine was significantly inhibited. In the non-inflamed group, morphine produced a dose-related place preference. A significant conditioning was observed at morphine doses of 4 and 8 mg/kg. Under these conditions, the morphineinduced place preference was significantly suppressed in inflamed groups compared with the non-inflamed group. The morphine-induced place preference in the inflamed group gradually recovered to the level of the non-inflamed group as the inflammation healed. Rats, with conditioning on the 14th day after the induction of inflammation showed a significant place preference by morphine, like non-inflamed rats. In the non-inflamed group, pretreatment with NTI, but not nor-BNI, significantly suppressed the morphine-induced place preference. By contrast, the attenuation of morphine-induced place preference in the inflamed group was reversed by the pretreatment with nor-BNI, but not NTI. Morphine at 8 mg/kg produced increases in DA turnover in the limbic forebrain of non-inflamed group. Under inflammatory nociception the increases
O PIOID
65
DEPENDENCE AND INTERACTION
in DA turnover in the limbic forebrain by morphine were significantly suppressed, and this suppression was reversed by the pretreatment with nor-BNI.
DISCUSSION In the present study, we found that inflammatory nociception produced by formalin and carrageenan inhibited the development of antinociceptive tolerance to morphine. As well as tolerance, the morphine-induced rewarding effect was significantly suppressed under chronic pain. Our findings are similar to the results of clinical experience in the use of morphine for relief of cancer pain (WHO, 1996). We also found that the suppression of the morphine-induced rewarding effect corresponds to the intensity of inflammatory nociception. It should be noted that the attenuation of morphine-induced place preference under inflammation was reversed by the pretreatment with -receptor antagonist but not -receptor antagonist. These results suggest that the activation of endogenous -opioid systems produced by the inflammatory nociception may contribute to the attenuation
of place preference induced by morphine in the presence of inflammatory nociception. It is well known that psychological dependence on morphine may be produced by the activation of mesolimbic DA system and this activation can be blocked by -receptor agonist (Funada et al., 1993). In the present study, we found that the increases in DA turnover in the limbic forebrain by morphine were significantly suppressed under inflammatory nociception, and the suppression was reversed by the pretreatment with -receptor antagonist. These results suggest that the attenuation of rewarding effect induced by morphine in the presence of inflammatory nociception may result from the inhibition of mesolimbic DA system by activated endogenous -opioid systems under inflammatory nociception.
REFERENCES Funada M, Suzuki T, Narita M, Misawa M, Nagase H. Blockade of morphine reward through the activation of -opioid receptors in mice. Neuropharmacology 1993; 32: 1315±1323. World Health Organization. Cancer Pain Relief. Geneva: World Health Organization, 1996: 14±37.
European Journal of Pain (2001), 5 (Suppl. A)