Original Article
Cholecystokinin-B Antagonist could Prevent and Reverse Repeated Morphine Injection-induced Antinociceptive Tolerance
Volume 30,Issue 1,Pages 7-18
Yu-Cheng Liu1 , Shang-Yi Lee1 , Hsin-Han Ouyang1 , Kuen Bao Chen1.2 , Yeong-Ray Wen1.2.3.4

1Pain Management and Research Center, Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan

2School of Medicine, China Medical University, Taichung, Taiwan

3Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan

4Acupuncture Research Center, China Medical University, Taichung, Taiwan

PDF

Outline

Abstract

Background

Paradoxical opioid-induced pain, an unusual hyperesthesia and allodynia, appears in human and animals after exposure to long-term morphine uses. Cholecystokinin (CCK) is an endogenous anti-opioid peptide and presumed to be involved in this phenomenon. In this study, we tested if CCK-B antagonist could ameliorate nociceptive hyperalgesia in the morphine-tolerant rats.
Materials and Methods: Male Sprague-Dawley rats subjective to morphine 4 mg/kg, s.c. twice daily for 4 days and another injection in the morning of the fifth day, developed morphine analgesic tolerance. LY225,910 (0.1, or 1 mg/kg, s.c.), a CCK-B receptor antagonist, or saline at 1.0 ml was injected 30 min before morphine treatment in separate groups. Two control groups of rats received saline or LY225,910 (1 mg/kg, s.c.) alone twice daily for 5 days. Intraplantar formaline injection at the left hind paw was conducted after the last morphine or saline injection on the 5th day morning. Formalin-induced paw hyperalgesic responses were evaluated and calculated by a weighted pain scoring software. Fos expression by immunohistochemistry at the L4-5 spinal dorsal horn were also analyzed.

Results

The morphine-tolerant rats showed significantly stronger formalininjection induced hyperalgesia compared to the normal rats, and co-treatment of LY225,910 with morphine attenuated morphine tolerance in a dose-dependent manner. The high-dose co-treatment group (1.0 mg/kg) showed a significant reduction in formalin-induced paw hyperalgesia, especially at the late phase response. Induction of Fos expression after formalin injection was higher in the morphine-treated rats compared to those in the saline or LY225,910 injection rats. Co-administration with LY225,910 at the high dose could decrease the Foslike immunoreactivity, but the low-dose group did not show difference from the morphine group.

Conclusion

We concluded that CCK-B antagonist LY225,910 could attenuate morphine tolerance-induced behavioral hyperalgesia and spinal Fos reactivity in the rats. The inhibition of Formalin-induced hyperalgesia may be mediated through reduction of spinal mechanism of the CCKergic pathway

Cholecystokinin, CCK antagonist, Formalin test, Morphine tolerance, Opioid-induced hyperalgesia

Key Words

Cholecystokinin, CCK antagonist, Formalin test, Morphine tolerance, Opioid-induced hyperalgesia



Download full text in PDF

References
1

Mao J, Price DD, Mayer DJ

Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C.

J Neurosci, 1994; 14: 2301-12.

Article CrossRef Scopus

2

Ossipov MH, Lopez Y, Nichols ML, Bian D, Porreca F

The loss of antinociceptive efficacy of spinal morphine in rats with nerve ligation injury is prevented by reducing spinal afferent drive.

Neurosci Lett, 1995; 199: 87-90.

Article CrossRef Scopus

3

Wegert S, Ossipov MH, Nichols ML, Bian D, Vanderah TW, Malan TP, Jr., Porreca F

Differential activities of intrathecal MK-801 or morphine to alter responses to thermal and mechanical stimuli in normal or nerve-injured rats.

Pain, 1997; 71: 57- 64.

Article CrossRef Scopus

4

Devulder J

Hyperalgesia induced by high-dose intrathecal sufentanil in neuropathic pain.

J Neurosurg Anesthesiol, 1997; 9: 146-8.

Article CrossRef Scopus

5

Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong CM, Zhang ET, Malan TP, Jr., Ossipov MH, Lai J, Porreca F

Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance.

J Neurosci, 2000; 20: 7074-9.

Article CrossRef

6

Celerier E, Laulin JP, Corcuff JB, Le Moal M, Simonnet G

Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration

a sensitization process. J Neurosci, 2001; 21: 4074-80

Article CrossRef Scopus

7

Fernandes M , Kluwe S , Coper H

The development of tolerance to morphine in the rat.

Psychopharmacology (Berl), 1977; 54: 197-201.

Article CrossRef

8

Fernandes M, Kluwe S, Coper H

Quantitative assessment of tolerance to and dependence on morphine in mice.

Naunyn Schmiedebergs Arch Pharmacol, 1977; 297: 53-60.

Article CrossRef Scopus

9

Mao J

NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity.

Brain Res Brain Res Rev, 1999; 30: 289-304.

Article CrossRef Scopus

10

Bekhit MH

Opioid-induced hyperalgesia and tolerance.

Am J Ther, 2010; 17: 498-510.

CrossRef

11

Mao J, Price DD, Mayer DJ

Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions.

Pain, 1995; 62: 259-74.

Article CrossRef Scopus

12

Woolf CJ

Intrathecal high dose morphine produces hyperalgesia in the rat.

Brain Res, 1981; 209: 491- 5.

Article CrossRef Scopus

13

Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G

Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine.

Anesthesiology, 2000; 92: 465-72.

Article CrossRef Scopus

14

Zhou Y, Sun YH, Zhang ZW, Han JS

Accelerated expression of cholecystokinin gene in the brain of rats rendered tolerant to morphine.

Neuroreport, 1992; 3: 1121-3.

Article CrossRef Scopus

15

Roques BP, Noble F

Association of enkephalin catabolism inhibitors and CCK-B antagonists: a potential use in the management of pain and opioid addiction.

Neurochem Res, 1996; 21: 1397-410.

Article CrossRef Scopus

16

Zhou Y, Sun YH, Zhang ZW, Han JS

Increased release of immunoreactive cholecystokinin octapeptide by morphine and potentiation of mu- opioid analgesia by CCKB receptor antagonist L-365,260 in rat spinal cord.

Eur J Pharmacol, 1993; 234: 147-54.

Article CrossRef Scopus

17

de Araujo Lucas G, Alster P, Brodin E, Wiesenfeld- Hallin Z

Differential release of cholecystokinin by morphine in rat spinal cord.

Neurosci Lett, 1998; 245: 13-6.

Article CrossRef Scopus

18

Faris PL, Komisaruk BR, Watkins LR, Mayer DJ

Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia.

Science, 1983; 219: 310-2.

Article CrossRef Scopus

19

Ossipov MH, Lai J, Vanderah TW, Porreca F

Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance.

Life Sciences, 2003; 73: 783-800.

Article CrossRef Scopus

20

Lu L, Huang M, Ma L, Li J

Different role of cholecystokinin (CCK)-A and CCK-B receptors in relapse to morphine dependence in rats.

Behavioural Brain Research, 2001; 120: 105-10.

Article CrossRef

21

Dourish CT, O’Neill MF, Coughlan J, Kitchener SJ, Hawley D, Iversen SD

The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat.

European Journal of Pharmacology, 1990; 176: 35-44.

Article CrossRef Scopus

22

Kellstein DE, Mayer DJ

Spinal co-administration of cholecystokinin antagonists with morphine prevents the development of opioid tolerance.

Pain, 1991; 47: 221-9.

Article CrossRef Scopus

23

Xu XJ, Wiesenfeld-Hallin Z, Hughes J, Horwell DC, Hokfelt T

CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat.

Br J Pharmacol, 1992; 105: 591-6.

Article CrossRef Scopus

24

Hughes J , Hunter JC , Woodruff GN

Neurochemical actions of CCK underlying the therapeutic potential of CCK-B antagonists.

Neuropeptides, 1991; 19 Suppl: 85-9.

Article CrossRef Scopus

25

Stanfa L, Dickenson A, Xu XJ, Wiesenfeld-Hallin Z

Cholecystokinin and morphine analgesia: variations on a theme.

Trends Pharmacol Sci, 1994; 15: 65-6.

Article CrossRef Scopus

26

Ossipov MH, Kovelowski CJ, Vanderah T, Porreca F

Naltrindole, an opioid delta antagonist, blocks the enhancement of morphine-antinociception induced by a CCKB antagonist in the rat.

Neurosci Lett, 1994; 181: 9-12.

Article CrossRef Scopus

27

Vanderah TW, Bernstein RN, Yamamura HI, Hruby VJ, Porreca F

Enhancement of morphine antinociception by a CCKB antagonist in mice is mediated via opioid delta receptors.

J Pharmacol Exp Ther, 1996; 278: 212-9.

Article CrossRef Scopus

28

Liu YC, Lee SY, Ouyang HH, Chen KB, Wen YR

Cholecystokinin-B Antagonist could Prevent and Reverse Repeated Morphine Injection-induced Antinociceptive Tolerance.

Taiwan J Pain, 2020 (accepted).

Article CrossRef

29

Silverman SM

Opioid induced hyperalgesia: clinical implications for the pain practitioner.

Pain Physician, 2009; 12: 679-84.

Article CrossRef Scopus

30

Angst MS, Clark JD

Opioid-induced hyperalgesia: a qualitative systematic review.

Anesthesiology, 2006; 104: 570-87.

Article CrossRef Scopus

31

Crofford LJ

Adverse effects of chronic opioid therapy for chronic musculoskeletal pain.

Nat Rev Rheumatol, 2010; 6: 191-7.

Article CrossRef

32

Hayhurst CJ, Durieux ME

Differential Opioid Tolerance and Opioid-induced Hyperalgesia A Clinical Reality.

Anesthesiology, 2016; 124: 483-8.

Article CrossRef Scopus

33

Roeckel LA, Le Coz GM, Gaveriaux-Ruff C, Simonin F

Opioid-induced hyperalgesia: Cellular and molecular mechanisms.

Neuroscience, 2016; 338: 160-82.

Article CrossRef

34

Mouledous L, Mollereau C, Zajac JM

Opioid- modulating properties of the neuropeptide FF system.

Biofactors, 2010; 36: 423-9.

Article CrossRef

35

Rothman RB

A review of the role of anti-opioid peptides in morphine tolerance and dependence.

Synapse, 1992; 12: 129-38.

Article CrossRef Scopus

36

McNally GP

Pain facilitatory circuits in the mammalian central nervous system: their behavioral significance and role in morphine analgesic tolerance.

Neurosci Biobehav Rev, 1999; 23: 1059-78.

Article CrossRef Scopus

37

Toll L, Bruchas MR, Calo G, Cox BM, Zaveri NT

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems.

Pharmacol Rev, 2016; 68: 419-57.

Article CrossRef Scopus

38

Becker C, Hamon M, Cesselin F, Benoliel JJ

Delta(2)-opioid receptor mediation of morphine- induced CCK release in the frontal cortex of the freely moving rat.

Synapse, 1999; 34: 47-54.

Article CrossRef

39

Xie JY, Herman DS, Stiller CO, Gardell LR, Ossipov MH, Lai J, Porreca F, Vanderah TW

Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance.

J Neurosci, 2005; 25: 409-16.

Article CrossRef Scopus

40

Noble F, Derrien M, Roques BP

Modulation of opioid antinociception by CCK at the supraspinal level: evidence of regulatory mechanisms between CCK and enkephalin systems in the control of pain.

British Journal of Pharmacology, 1993; 109: 1064-70.

Article CrossRef Scopus

41

Wiesenfeld-Hallin Z, Xu XJ

The role of cholecystokinin in nociception, neuropathic pain and opiate tolerance.

Regul Pept, 1996; 65: 23-8.

Article CrossRef Scopus

42

Ambriz-Tututi M, Cruz SL, Urquiza-Marin H, Granados-Soto V

Formalin-induced long- term secondary allodynia and hyperalgesia are maintained by descending facilitation.

Pharmacol Biochem Behav, 2011; 98: 417-24.

Article CrossRef Scopus

43

Coudore-Civiale MA, Courteix C, Fialip J, Boucher M, Eschalier A

Spinal effect of the cholecystokinin-B receptor antagonist CI-988 on hyperalgesia, allodynia and morphine-induced analgesia in diabetic and mononeuropathic rats.

Pain, 2000; 88: 15-22.

Article CrossRef Scopus

44

DeSantana JM, da Silva LF, Sluka KA

Cholecystokinin receptors mediate tolerance to the analgesic effect of TENS in arthritic rats.

Pain, 2010; 148: 84-93.

Article CrossRef Scopus

45

Kim J, Kim JH, Kim Y, Cho HY, Hong SK, Yoon YW

Role of spinal cholecystokinin in neuropathic pain after spinal cord hemisection in rats.

Neurosci Lett, 2009; 462: 303-7.

Article CrossRef Scopus