Potentiation of Morphine-Induced Antinociception by Propranolol: The Involvement of Dopamine and GABA Systems

Elham A Afify, Najlaa M Andijani, Elham A Afify, Najlaa M Andijani

Abstract

Tolerance to the analgesic effect of morphine is a major clinical problem which can be managed by co-administration of another drug. This study investigated the ability of propranolol to potentiate the antinociceptive action of morphine and the possible mechanisms underlying this effect. Antinociception was assessed in three nociceptive tests (thermal, hot plate), (visceral, acetic acid), and (inflammatory, formalin test) in mice and quantified by measuring the percent maximum possible effect, the percent inhibition of acetic acid-evoked writhing response, and the area under the curve values of number of flinches for treated mice, respectively. The study revealed that propranolol (0.25-20 mg/Kg, IP) administration did not produce analgesia in mice. However, 10 mg/Kg propranolol, enhanced the antinociceptive effect of sub-analgesic doses of morphine (0.2, 1, and 2 mg/Kg, IP) in the three nociceptive tests. It also shifted the dose response curve of morphine to the left. The combined effect of propranolol and morphine was attenuated by haloperidol (D2 receptor antagonist, 1.5 mg/Kg, IP), and bicuculline (GABAA receptor antagonist, 2 mg/Kg, IP). Repeated daily administration of propranolol (10 mg/Kg, IP) did not alter the nociceptive responses in the three pain tests, but it significantly potentiated morphine-induced antinociception in the hot plate, acetic acid-evoked writhing, and in the second phase of formalin tests. Together, the data suggest that a cross-talk exists between the opioidergic and adrenergic systems and implicate dopamine and GABA systems in this synergistic effect of morphine-propranolol combination. Propranolol may serve as an adjuvant therapy to potentiate the effect of opioid analgesics.

Keywords: D2 receptors; GABAA receptors; acetic acid; antinociception; formalin; hot plate; opioids; propranolol.

Figures

FIGURE 1
FIGURE 1
The treatment regimen in different pain models.
FIGURE 2
FIGURE 2
Effects of administration of morphine (Mor) and propranolol [Pro, 10 mg/Kg, intraperitoneally (IP)] either alone or in combination on acetic acid-evoked writhing in mice. (A) The dose-response curve for the antinociceptive effect of morphine alone (0.2–8 mg/Kg, IP) and morphine-propranolol combination. (B–D) The antinociceptive effect of Mor, Pro and their combination. (E) The effect of pretreatment with the dopamine receptor antagonist haloperidol (Hal, 1.5 mg/Kg, IP) and GABAA receptor antagonist bicuculline (Bic, 2 mg/Kg, IP) on the antinociceptive effect of morphine-propranolol combination. Each point represents the mean of % inhibition of acetic acid-evoked writhing ± SE for 6–8 mice. ∗P < 0.05 compared with control, #P < 0.05 compared with Mor 1 mg/Kg (B), Mor 2 mg/Kg (C), Mor 4 mg/Kg (D,E), +P < 0.05 compared with Mor-Pro group, by one-way ANOVA and Bonferroni’s post hoc test.
FIGURE 3
FIGURE 3
Effect of administration of propranolol (Pro, 10 mg/Kg, IP) on the antinociceptive effect of morphine (Mor) in the hot plate test represented by percent maximum possible effect (%MPE). (A) The dose–response curve for the antinociceptive effect of morphine alone (0.2–8 mg/Kg, IP) and morphine-propranolol combination. (B,C) The antinociceptive effect of different doses of morphine, propranolol and their combination. (D) The effect of pretreatment with dopamine receptor antagonist haloperidol (Hal, 1.5 mg/Kg, IP) and bicuculline, GABAA receptor antagonist (Bic, 2 mg/Kg, IP) on the antinociceptive effect of morphine-propranolol combination. Each point indicated the mean %MPE ± SE for 6–8 mice. ∗P < 0.05 compared with control, #P < 0.05 compared with Mor 1 mg/Kg, +P < 0.05 compared with Mor-Pro group, by one-way ANOVA and Bonferroni’s post hoc test.
FIGURE 4
FIGURE 4
Effect of administration of morphine (Mor, 0.2 mg/Kg, IP) and propranolol (Pro, 10 mg/Kg, IP) on the hind paw flinches quantified during the two phases of the formalin test in mice during the first phase (A) and second phase (B) of the test. The effect of pretreatment with haloperidol, dopamine receptor antagonist (Hal, 1.5 mg/Kg, IP) on the antinociceptive effect of morphine-propranolol combination during both first and second phases (C,D), respectively. Each point represents the mean area under the curve (AUC) for the number of flinches ± SE for 6–8 mice. ∗P < 0.05 compared with control, #P < 0.05 compared with Mor 0.2 mg/Kg, +P < 0.05 compared with Mor-Pro group, by one-way ANOVA and Bonferroni’s post hoc test.
FIGURE 5
FIGURE 5
Scheme for cross-talk between opioid, adrenergic and D2 dopamine receptors that may lead to the potentiation of opioid antinociception after treatment with propranolol. Stimulatory effects are indicated by green arrows/lines, inhibitory effects in red arrows/lines, the potentiating effects are shown in thick dashed green lines. Agonist stimulation of β-adrenergic receptors activates (AC) and stimulates (PKA). Morphine acting on opioid receptors activates G i/o proteins, which blunts the recruitment of PKA via inhibiting (AC) and reducing the level of cAMP. Blocking of β-adrenergic receptors by propranolol and stimulation of opioid receptors by morphine reduce cellular cAMP and potentiate the antinociceptive response. Blocking of the D2 receptors by haloperidol prevents the inhibitory effect of dopamine on AC enzyme and the reduction in cAMP level and antagonizes the inhibitory effect of morphine and propranolol on reducing cAMP level and reversed their antinociceptive effect. BAR, β-adrenergic receptors; ORP, opioid receptors; Gs, stimulatory G-protein; Gi, inhibitory G protein; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.

References

    1. Afify E., Alkreathy H., Ali A., Alfaifi H., Khan L. (2017). Characterization of the antinociceptive mechanisms of khat extract (Catha edulis) in mice. Front. Neurol. 8:69. 10.3389/fneur.2017.00069
    1. Afify E., Khedr M., Omar A., Nasser S. (2013). The involvement of K (ATP) channels in morphine-induced antinociception and hepatic oxidative stress in acute and inflammatory pain in rats. Fundam. Clin. Pharmacol. 27 623–631. 10.1111/fcp.12004
    1. Almeida-Santos A. F., Ferreira R. C., Duarte I. D., Aguiar D. C., Romero T. R., Moreira F. A. (2015). The antipsychotic aripiprazole induces antinociceptive effects: possible role of peripheral dopamine D2 and serotonin 5-HT1A receptors. Eur. J. Pharmacol. 765 300–306. 10.1016/j.ejphar.2015.08.053
    1. Benish M., Bartal I., Goldfarb Y., Levi B., Avraham R., Raz A., et al. (2008). Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann. Surg. Oncol. 15 2042–2052. 10.1245/s10434-008-9890-5
    1. Benistant C., Rey C., Fonlupt P., Pacheco H. (1988). Interaction of propranolol with GABA stimulated diazepam binding to rat brain membranes. Gen. Pharmacol. 19 537–539. 10.1016/0306-3623(88)90160-7
    1. Carlton S. M., Zhou S. (1998). Attenuation of formalin-induced nociceptive behaviours following local peripheral injection of gabapentin. Pain 76 201–207. 10.1016/S0304-3959(98)00043-8
    1. Carlton S. M., Zhou S., Coggeshall R. E. (1999). Peripheral GABAA receptors: evidence for peripheral primary afferent depolarization. Neuroscience 93 713–722. 10.1016/S0306-4522(99)00101-3
    1. Chen Y. W., Chiu C. C., Wei Y. L., Hung C. H., Wang J. J. (2015). Propranolol combined with dopamine has a synergistic action in intensifying and prolonging cutaneous analgesia in rats. Pharmacol. Rep. 67 1224–1229. 10.1016/j.pharep.2015.05.016
    1. Chen Y. W., Chu C. C., Chen Y. C., Hung C. H., Wang J. J. (2012). Propranolol elicits cutaneous analgesia against skin nociceptive stimuli in rats. Neurosci. Lett. 524 129–132. 10.1016/j.neulet.2012.07.036
    1. Chia Y. Y., Chan M. H., Ko N. H., Liu K. (2004). Role of β-blockade in anaesthesia and postoperative pain management after hysterectomy. Br. J. Anaesth. 93 799–805. 10.1093/bja/aeh268
    1. Clarke P. B., Franklin K. B. (1992). Infusion of 6-hydroxydopamine into nucleus accumbens abolish the analgesic effect of amphetamine but not of MOR in the formalin test. Brain Res. 580 106–110. 10.1016/0006-8993(92)90932-Y
    1. Cobacho N., Calle J. L., Paíno C. L. (2014). Dopaminergic modulation of neuropathic pain: analgesia in rats by a D2-type receptor agonist. Brain Res. Bull. 106 62–71. 10.1016/j.brainresbull.2014.06.003
    1. Collard V., Mistraletti G., Asenjo J. F., Feldman L. S., Fried G. M., Carli F. (2007). Intraoperative esmolol infusion in the absence of opioids spares postoperative fentanyl in patients undergoing ambulatory laparoscopic cholecystectomy. Anesth. Analg. 105 1255–1262. 10.1213/01.ane.0000282822.07437.02
    1. Coloma M., Chiu J. W., White P. F., Armbruster S. C. (2001). The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-tract outpatient gynecologic laparoscopic surgery. Anesth. Analg. 92 352–357. 10.1213/00000539-200102000-00014
    1. Dai W. L., Xiong F., Yan B., Cao Z. U., Liu W. T., Liu J. H., et al. (2016). Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord. Sci. Rep. 6:38746. 10.1038/srep38746
    1. Damaj M. (2007). Behavioral modulation of neuronal calcium/calmodulin-dependent protein kinase II activity: differential effects on nicotine-induced spinal and supraspinal antinociception in mice. Biochem. Pharmacol. 74 1247–1252. 10.1016/j.bcp.2007.07.008
    1. Danielsson J., Zaidi S., Kim B., Funayama H., Yim P. D., Xu D., et al. (2016). Airway epithelial cell release of GABA is regulated by protein kinase A. Lung 194 401–408. 10.1007/s00408-016-9867-2
    1. Degoute C. S. (2007). Controlled hypotension: a guide to drug choice. Drugs. 67 1053–1076. 10.2165/00003495-200767070-00007
    1. Deten A., Volz H. C., Holzl A., Briest W., Zimmer H. G. (2003). Effect of propranolol on cardiac cytokine expression after myocardial infarction in rats. Mol. Cell Biochem. 251 127–137. 10.1023/A:1025498319598
    1. Dolan S., Nolan A. M. (2001). Biphasic modulation of nociceptive processing by the cyclic AMP-protein kinase A signalling pathway in sheep spinal cord. Neurosci. Lett. 309 157–160. 10.1016/S0304-3940(01)02063-8
    1. Fávaro-Moreira N. C., Parada C. A., Tambeli C. H. (2012). Blockade of β1-, β2- and β3-adrenoceptors in the temporomandibular joint induces antinociception especially in female rats. Eur. J. Pain 16 1302–13010. 10.1002/j.1532-2149.2012.00132.x
    1. Fennessy M. R., Lee J. R. (1970). Modification of morphine analgesia by drugs affecting adrenergic and tryptaminergic mechanisms. J. Pharm. Pharmac. 22 930–935. 10.1111/j.2042-7158.1970.tb08475.x
    1. Garcely R. (1995). “Studies of pain in normal man,” in Textbook of Pain 3rd Edn eds Melzack R., Wall P. (London: Churchill Livingstone; ) 315–336.
    1. Gorlitz B. D., Frey H. H. (1972). Central monoamines and antinociceptive drug action. Eur. Z. Pharmac. 20 171–180. 10.1016/0014-2999(72)90146-X
    1. Grimm M., Brown J. H. (2010). β-Adrenergic receptor signaling in the heart: role of CaMKII. J. Mol. Cell Cardiol. 48 322–330. 10.1016/j.yjmcc.2009.10.016
    1. Haghighi M., Sedighinejad A., Mirbolook A., Nabi B., Farahmand M., Kazemnezhad E., et al. (2015). Effect of intravenous intraoperative esmolol on pain management following lower limb orthopedic surgery. Korean J. Pain 28 198–202. 10.3344/kjp.2015.28.3.198
    1. Hajighasemi F., Mirshafiey A. (2010). In vitro effects of propranolol on T helper type 1 cytokine profile in human leukemic T cells. Int. J. Hematol. Oncol. Stem Cell Res. 10 99–105.
    1. Hajighasemi F., Mirshafiey A. (2016). Propranolol effect on proliferation and vascular endothelial growth factor secretion in human immunocompetent cells. J. Clin. Immunol. Immunopathol. Res. 2 22–27.
    1. Harris G. C., Aston-Jones G. (1993). Beta-adrenergic antagonists attenuate somatic and aversive signs of opiate withdrawal. Neuro Psychopharmacol. 9 303–311. 10.1038/npp.1993.66
    1. Hemnani T. J., Khan I. M., Patki V. P., Dashputra P. G. (1983). Effect of diphenyl-hydantoin with diazepam on electoseizure and chemoseizure susceptibility in mice. Indian J. Med. Res. 77 521–524.
    1. Hunskaar S., Hole K. (1987). The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30 103–114. 10.1016/0304-3959(87)90088-1
    1. Kaneto H., Inoue M. (1990). Action site of adrenergic blockers to suppress the development of tolerance to morphine analgesia. Brain Res. 507 35–39. 10.1016/0006-8993(90)90518-G
    1. Kato H., Kawaguchi M., Inoue S., Hirai K., Furuya H. (2009). The effects of beta-adrenoceptor antagonists on proinflammatory cytokine concentrations after subarachnoid hemorrhage in rats. Anesth. Analg. 108 288–295. 10.1213/ane.0b013e318187bb93
    1. Khanna N., Malhotra R. S., Mehta A. K., Garg G. R., Halder S., Sharma K., et al. (2011). Interaction of morphine and potassium channel openers on experimental models of pain in mice. Fundam. Clin. Pharmacol. 25 479–484. 10.1111/j.1472-8206.2010.00880.x
    1. Kihara T., Kaneto H. (1986). Important role of adrenergic function in the development of analgesic tolerance to morphine in mice. Jpn. J. Pharmacol. 42 419–423. 10.1254/jjp.42.419
    1. Koelemay M. J., Legemate D. A. (2008). Perioperative beta-blockade for reduction of cardiovascular complications in non-cardiac surgery: advantages and disadvantages. Ned. Tijdschr. Geneeskd. 152 2603–2605.
    1. Koster R., Anderson M., De Beer E. J. (1959). Acetic acid for analgesic screening. Fed. Proc. 18 412–416.
    1. Kumar R., Mehra R. D., Ray B. S. (2010). L-type calcium channel blockers, morphine and pain: newer insights. Indian J. Anaesth. 54 127–131. 10.4103/0019-5049.63652
    1. Law P. Y., Loh H. H. (1999). Regulation of opioid receptor activities. J. Pharmacol. Exp. Ther. 289 607–624.
    1. Li Q. Q., Shi G. X., Yang J. W., Li Z. X., Zhang Z. H., He T., et al. (2015). Hippocampal cAMP/PKA/CREB is required for neuroprotective effect of acupuncture. Physiol. Behav. 139 482–490. 10.1016/j.physbeh.2014.12.001
    1. Liang D. Y., Shi X., Li X., Li J., Clark D. (2007). The β2 adrenergic receptor regulates morphine tolerance and physical dependence. Behav. Brain Res. 181 118–126. 10.1016/j.bbr.2007.03.037
    1. Motta P. G., Veiga A. P. C., Francischi J. N., Tatsuo M. (2004). Evidence for participation of GABAA receptors in a rat model of secondary hyperalgesia. Eur. J. Pharmacol. 483 233–239. 10.1016/j.ejphar.2003.10.015
    1. Nestler E. J. (1996). Under siege: the brain on opiates. Neuron 16 897–900. 10.1016/S0896-6273(00)80110-5
    1. Nguyen L. P., Omoluabi O., Parra S., Frieske J. M., Clement C., Ammar- Aouchiche Z., et al. (2008). Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model. Am. J. Respir. Cell Mol. Biol. 38 256–262. 10.1165/rcmb.2007-0279RC
    1. Omar A. S. (2007). Modulation of visceral nociception, inflammation and gastric mucosal injury by cinnarazine. Drug Target Insights 2 29–38.
    1. Oprée A., Kress M. (2000). Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. J. Neurosci. 20 6289–6293.
    1. Pajot J., Pelissier T., Sierralta F., Raboisson P., Dallel R. (2000). Differential effects of trigeminal tractotomy on Adelta- and C-fiber-mediated nociceptive responses. Brain Res. 863 289–292. 10.1016/S0006-8993(00)02157-0
    1. Pepe S., Brink O. W., Lakatta E. G., Xiao R. P. (2004). Cross-talk of opioid peptide receptor and beta-adrenergic receptor signalling in the heart. Cardiovasc. Res. 63 414–422. 10.1016/j.cardiores.2004.04.022
    1. Rangel-Barajas C., Coronel I., Florán B. (2015). Dopamine receptors and neurodegeneration. Aging Dis. 6 349–368. 10.14336/AD.2015.0330
    1. Reisi Z., Haghparast A., Pahlevani P., Shamsizadeh A., Haghparast A. (2014). Interaction between the dopaminergic and opioidergic systems in dorsal hippocampus in modulation of formalin-induced orofacial pain in rats. Pharmacol. Biochem. Behav. 124 220–225. 10.1016/j.pbb.2014.06.015
    1. Richard E. C., William L. D., Louis S. H., Werner L. (1975). Effect of propranolol on antinociceptive and withdrawal characteristics of morphine. Pharmacol. Biochem. Behav. 3 843–847. 10.1016/0091-3057(75)90115-X
    1. Ringkamp M., Schepers R. J., Shimada S. G., Johanek L. M., Hartke T. V., Borzan J., et al. (2011). A role for nociceptive, myelinated nerve fibers in itch sensation. J. Neurosci. 31 14841–14849. 10.1523/JNEUROSCI.3005-11.2011
    1. Sehgal N., Colson J., Smith H. S. (2013). Chronic pain treatment with opioid analgesics: benefits versus harms of long-term therapy. Expert Rev. Neurother. 13 1201–1220. 10.1586/14737175.2013.846517
    1. Shao X. M., Sun J., Jiang Y. L., Liu B. Y., Shen Z., Fang F., et al. (2016). Inhibition of the cAMP/PKA/CREB pathway contributes to the analgesic effects of electroacupuncture in the anterior cingulate cortex in a rat pain memory model. Neural Plast. 2016:5320641. 10.1155/2016/5320641
    1. Smith H. (2006). beta blockers as analgesic adjuvants. J. Neuropathic Pain Symptom palliat. 1 21–24. 10.1300/J426v01n04_04
    1. Song X. J., Wang Z. B., Gan Q., Walters E. T. (2006). cAMP and cGMP contribute to sensory neuron hyperexcitability and hyperalgesia in rats with dorsal root ganglia compression. J. Neurophysiol. 95 479–492. 10.1152/jn.00503.2005
    1. Tang F. K., Hua N., Lu H., Xiao J., Tang X. Z., Qi Z. (2008). Effects of bisoprolol on serum interleukin-6 and tumor necrosis factor-alpha level in patients with congestive heart failure. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 24 1177–1179.
    1. Vamecq J., Mention-Mulliez K., Leclerc F., Dobbelaere D. (2015). Opioid facilitation of β-adrenergic blockade: a new pharmacological condition? Pharmaceuticals 8 664–674. 10.3390/ph8040664
    1. Wood P. B. (2008). Role of central dopamine in pain and analgesia. Expert Rev. Neurother. 8 781–797. 10.1586/14737175.8.5.781
    1. Wood P. L. (1983). Opioid regulation of CNS dopaminergic pathways: a review of methodology, receptor types, regional variations and species differences. Peptides 4 595–601. 10.1016/0196-9781(83)90003-7
    1. Woolfe G., MacDonald A. D. (1944). The evaluation of the analgesic action of pethidine hydrochloride. J. Pharmacol. Exp. Ther. 80 300–307.
    1. Xiao C., Zhou C., Atlas G., Delphin E., Ye J. (2008). Labetalol facilitates GABAergic transmission in rat periaqueductal gray neurons via antagonizing B1- adrenergic receptors - possible mechanism underlying labetalol-induced analgesia. Brain Res. 198 34–43. 10.1016/j.brainres.2008.01.023
    1. Zaugg M., Tagliente T., Lucchinetti E., Jacobs E., Krol M., Bodian C., et al. (1999). Beneficial effects from beta-adrenergic blockade in elderly patients undergoing noncardiac surgery. Anesthesiology 91 1674–1686. 10.1097/00000542-199912000-00020
    1. Zheng H., Loh H. H., Law P.-Y. (2010). Agonist-selective signaling of G protein-coupled receptor: mechanisms and Implications. IUBMB Life 62 112–119. 10.1002/iub.293

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