슬라이드 1

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1 Opioids: Blessing and Curse Ki-Wan Oh, PhD. College of Pharmacy, Chungbuk National University

3 Among the remedies, which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and as efficacious as opium. - Thomas Sydenham -

4 They offered Jesus wine to drink, mixed with gall: but after tasting it, he refused to drink it. (Matthew 27:34) Then they offered him wine mixed myrrh, but he did not take it. (Mark 15: 23) Jesus said, I am thirsty. A jar of wine vinegar was there, so they soaked a sponge in it. (John 19:29)

(Matthew 27:34) Then they offered him wine mixed myrrh, but he did not

5 History of Opiate Research 1806, Serturner, named morphine after Morpheus, The Greek god of dreams. 1954, Beckett and Cays, opiate ligands. 1972, Akil, reversal by naloxone. 1973, Pert and Snyder, opiate binding sites. 1976, Martin et al., multiple opiate receptors. 1994, Bunzow et al., opioid receptors cloned.

1972, Akil, reversal by naloxone. 1973, Pert and Snyder, opiate binding sites.

6 Analgesic mechanisms of morphine Supraspinal pain control mechanism

7 Opioid subtypes and their functions Receptors Subtypes μ (mu) δ (delta) Functions Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed gastrointestinal transit; modulation of hormone and neurotransmitter release Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release Endogenous Opioid- Peptide Affinity Endorphins > enkephalins > dynorphins Enkephalins > endorphins and dynorphins κ (kappa) Supraspinal and spinal analgesia; psychotomimetic effects; showed gastrointestinal transit Dynorphins >> endorphins and enkephalins

hormone and neurotransmitter release Endogenous Opioid- Peptide Affinity Endorphins > enkephalins > dynorphins Enkephalins > endorphins and

8 신체적 의존성 약물투여를 중단하였을 때 나타나는 불쾌감을 제거하기 위해서 약물을 찾는 행동 정신적 의존성 약물 복용에 향한 강력한 욕구, 약물 사용 조절의 어려움.

9 Mechanisms of morphine dependence 1) Opiate actions in the locus coeruleus (LC) 2) Up-regulation of the camp pathway

10 Drug Abuse in Korea 시대 주요 남용 약물 사회문제 관련법 일제점령기 이전 아편 아편 중독자 발생 일제점령기 헤로인, 아편, 몰핀 마약 중독자 증가 조선 아편 취체령 1945년 헤로인, 아편 마약 중독자 증가 마약 취체령 1950년대 아편 아편 중독자 증가 마약법 1960년대 아편, 메사돈 메사돈 중독자 발생 및 증가 (메사돈 파동) 마약법 1970년대 대마초, 필로폰, LSD 젊은 층과 연예인들의 대마초 흡연 및 필로폰 밀조범 증가 습관성의약품 관리법 대마 관리법 1980년대 필로폰, 대마초, 본드 필로폰 중독자 증가 향정신성의약품관리법 대마 관리법 독 극물에 관한 법률 1990년대 필로폰, 대마초, 부탄가스, 본드 신종 마약류 출현 및 부탄 가스, 본드 중독 자 증가 (필로폰 제조 근절) 향정신성의약품 관리법 대마 관리법 유해화학물질 관리법 2000년-현재 필로폰, 야바, 엑스터시 신종 마약류 중독자 증가 마약류 관리에 관한 법률 (법률통합)

필로폰 밀조범 증가 습관성의약품 관리법 대마 관리법 1980년대 필로폰, 대마초, 본드 필로폰 중독자 증가 향정신성의약품관리법 대마 관리법 독 극물에 관한 법률 1990년대 필로폰, 대마초, 부탄가스, 본드 신종

11 Up-regulation of the camp pathway in opiate addiction Site of upregulation Locus coeruleus (LC) Ventral tegmental area Periaqueductal gray Nucleus accumbens Amygdala Dorsal horn of spinal cord Myenteric plexus of gut Functional consequence Physical dependence and withdrawal Dysphoria during early withdrawal periods Dysphoria during early withdrawal periods, Dysphoria during early withdrawal periods Conditioned aspects of addiction Tolerance to opiate-induced analgesia Tolerance to opiate-induced reduction in intestinal motility and increase in motility during withdrawal

Dysphoria during early withdrawal periods Dysphoria during early withdrawal periods, Dysphoria during early withdrawal periods Conditioned

12 Opiate actions in the locus coeruleus (LC)

13 Opiate actions in the locus coeruleus (LC)

14 Upregulation of the camp pathway

15 신체적 의존성의 평가 1) 마약 수용체 결합 실험 2) Naloxone precipitation 3) Makers

16 Morphine Physical Dependence Methods 1. 4 Weeks C57/BL/6 mouse were used and were assigned into 4 groups (n=9-13 for each group). 2. Morphine HCl (5, 10 and 20 mg/kg, s.c ) was injected twice daily at 12 h intervals (8:00 and 20:00) for 7 days. 3. After the final injections of morphine, mice were precipitated by naloxone (5 mg/kg). Just after the naloxone injection, mice were placed in acryl cylinder (diameter : 10cm, height : 30cm). 4. Withdrawal signs such as jumping, rearing, chattering, wet dog shakes, ptosis, scratching, licking penis, tremor, diarrhea and weight loss were observed 30 min and evaluated.

After the final injections of morphine, mice were precipitated by naloxone (5 mg/kg).

17 Naloxone precipitation (morphine I.c.v. infusion) Osmotic minipump를 이용 Morphine (200 μl, 10 μg/μl) 충진 정상 유출속도 1 μl/hr로 함. Satinless steel injector를 부착한 tygon tube를 minipump에 부착. 수술 1주일 후, 회복된 rat의 견갑골 사이의 피하에 minipump를 이식 Stainless steel injector를 guide cannulae에 연결 약물을 좌측뇌실에 7일간 주입

1 μl/hr로 함. Satinless steel injector를 부착한 tygon tube를 minipump에 부착.

18 Morphine Physical Dependence Behavior Score Number of Behavior Rearing Teeth Chattering Wet shakes Ptosis 1 points Scratching Licking penis Forepaw Tremor Escape behavior(jumping) Diarrhea 2 points Before After weight loss percent(%) Weight loss (naloxone injection)

Licking penis Forepaw Tremor Escape behavior(jumping) Diarrhea 2

Morphine Physical Dependence Methods 1. 4 Weeks C57/BL/6 mouse were used and were assigned into 4 groups (n=9-13 for each group). 2. Morphine HCl (5, 10 and 20 mg/kg, s.

19 Morphine Physical Dependence Methods 1. 4 Weeks C57/BL/6 mouse were used and were assigned into 4 groups (n=9-13 for each group). 2. Morphine HCl (5, 10 and 20 mg/kg, s.c ) was injected twice daily at 12 h intervals (8:00 and 20:00) for 7 days. 3. After the final injections of morphine, mice were precipitated by naloxone (5 mg/kg). Just after the naloxone injection, mice were placed in acryl cylinder (diameter : 10cm, height : 30cm). 4. Withdrawal signs such as jumping, rearing, chattering, wet dog shakes, ptosis, scratching, licking penis, tremor, diarrhea and weight loss were observed 30 min and evaluated.

20 Naloxone precipitation abstinence signs in morphine-dependent rats.

21 Morphine Physical Dependence Escape behavior (Jumping) con Morphine (s.c) Naloxone 5 mg/kg (i.p) Rearing mg/kg con Morphine (s.c) Naloxone 5 mg/kg (i.p) Teeth chattering * 2 0 mg/kg con Morphine (s.c) Naloxone 5 mg/kg (i.p) mg/kg Wet shakes ** ** Ptosis 2 1 * * Scratching * 0 con Morphine (s.c) mg/kg 0 con Morphine (s.c) 0 mg/kg con Morphine (s.c) mg/kg Naloxone 5 mg/kg (i.p) Naloxone 5 mg/kg (i.p) Naloxone 5 mg/kg (i.p) *p<0.05, **p<0.01, p<0.005 compared with saline group.

22 Morphine Physical Dependence Licking penis 10 5 ** Forepaw tremor con Morphine (s.c) mg/kg 0 con Morphine (s.c) mg/kg Naloxone 5 mg/kg (i.p) Naloxone 5 mg/kg (i.p) Diarrhea Weight loss (%) * 0 con mg/kg con mg/kg Morphine (s.c) Morphine (s.c) Naloxone 5 mg/kg (i.p) Naloxone 5 mg/kg (i.p) *p<0.05, **p<0.01, p<0.005 compared with saline group.

23 Morphine Physical Dependence Withdrawal total scores con Morphine (s.c) Naloxone 5 mg/kg (i.p) mg/kg p<0.005 compared with saline group.

24 Expression of p-creb by Western blot P-CREB β-actin Con Nal Mor5 Mor10 Mor20 +Nal +Nal +Nal p-creb protein level (p-creb/beta actin) ** * * Con mg/kg Morphine Naloxone 5 mg/kg Nal : Naloxone, Mor : Morphine. Each column represents the meas with S.E.M. * P<0.05, **P<0.01, compared with control.

25 Morphine is still the best remedy which God gives man to get rid of physical and psychological pain, if people would do not abuse this drug for euphoria, because dependence dose not develop in patients. (Ki-Wan Oh, 2010)

26 Thank you for your attention

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