No antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol in male and female rats with persistent inflammatory pain.
Analgesics, Non-Narcotic
/ administration & dosage
Analgesics, Opioid
/ administration & dosage
Animals
Disease Models, Animal
Dose-Response Relationship, Drug
Dronabinol
/ administration & dosage
Female
Freund's Adjuvant
Hyperalgesia
/ drug therapy
Inflammation
/ drug therapy
Locomotion
/ drug effects
Male
Morphine
/ administration & dosage
Pain
/ drug therapy
Pain Threshold
/ drug effects
Rats
Rats, Sprague-Dawley
Sex Factors
Journal
Behavioural pharmacology
ISSN: 1473-5849
Titre abrégé: Behav Pharmacol
Pays: England
ID NLM: 9013016
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
pubmed:
26
9
2021
medline:
25
2
2022
entrez:
25
9
2021
Statut:
ppublish
Résumé
Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.
Identifiants
pubmed: 34561365
doi: 10.1097/FBP.0000000000000657
pii: 00008877-202112000-00003
pmc: PMC8578411
mid: NIHMS1738921
doi:
Substances chimiques
Analgesics, Non-Narcotic
0
Analgesics, Opioid
0
Morphine
76I7G6D29C
Dronabinol
7J8897W37S
Freund's Adjuvant
9007-81-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
630-639Subventions
Organisme : NIDA NIH HHS
ID : T32 DA035200
Pays : United States
Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Références
Abboud C, Duveau A, Bouali-Benazzouz R, Massé K, Mattar J, Brochoire L, et al. (Animal models of pain: diversity and benefits. J Neurosci Methods 2021). 348:108997.
Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL (Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 2011). 90:844–851.
Alsalem M, Altarifi A, Haddad M, Azab B, Kalbouneh H, Imraish A, et al. (Analgesic effects and impairment in locomotor activity induced by cannabinoid/opioid combinations in rat models of chronic pain. Brain Sci 2020). 10:E523.
Altun A, Yildirim K, Ozdemir E, Bagcivan I, Gursoy S, Durmus N (Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists. J Physiol Sci 2015). 65:407–415.
Amaya F, Shimosato G, Kawasaki Y, Hashimoto S, Tanaka Y, Ji RR, Tanaka M (Induction of CB1 cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB1 agonist. Pain 2006). 124:175–183.
Averitt DL, Eidson LN, Doyle HH, Murphy AZ (Neuronal and glial factors contributing to sex differences in opioid modulation of pain. Neuropsychopharmacology 2019). 44:155–165.
Baamonde AI, Hidalgo A, Andrés-Trelles F (Sex-related differences in the effects of morphine and stress on visceral pain. Neuropharmacology 1989). 28:967–970.
Babalonis S, Lofwall MR, Sloan PA, Nuzzo PA, Fanucchi LC, Walsh SL (Cannabinoid modulation of opioid analgesia and subjective drug effects in healthy humans. Psychopharmacology (Berl) 2019). 236:3341–3352.
Babalonis S, Walsh SL (Therapeutic potential of opioid/cannabinoid combinations in humans: review of the evidence. Eur Neuropsychopharmacol 2020). 36:206–216.
Baker L, Ratka A (Sex-specific differences in levels of morphine, morphine-3-glucuronide, and morphine antinociception in rats. Pain 2002). 95:65–74.
Bartok RE, Craft RM (Sex differences in opioid antinociception. J Pharmacol Exp Ther 1997). 282:769–778.
Blanton HL, Barnes RC, McHann MC, Bilbrey JA, Wilkerson JL, Guindon J (Sex differences and the endocannabinoid system in pain. Pharmacol Biochem Behav 2021). 202:173107.
Blyth FM, March LM, Brnabic AJ, Jorm LR, Williamson M, Cousins MJ (Chronic pain in Australia: a prevalence study. Pain 2001). 89:127–134.
Britch SC, Goodman AG, Wiley JL, Pondelick AM, Craft RM (Antinociceptive and immune effects of delta-9-tetrahydrocannabinol or cannabidiol in male versus female rats with persistent inflammatory pain. J Pharmacol Exp Ther 2020). 373:416–428.
Britch SC, Wiley JL, Yu Z, Clowers BH, Craft RM (Cannabidiol-Δ9-tetrahydrocannabinol interactions on acute pain and locomotor activity. Drug Alcohol Depend 2017). 175:187–197.
Candido J, Lutfy K, Billings B, Sierra V, Duttaroy A, Inturrisi CE, Yoburn BC (Effect of adrenal and sex hormones on opioid analgesia and opioid receptor regulation. Pharmacol Biochem Behav 1992). 42:685–692.
Center for Behavioral Health Statistics and Quality (2017 National Survey on Drug Use and Health: Detailed Tables. 2018). https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHDetailedTabs2017/NSDUHDetailedTabs2017.pdf .
Cepeda MS, Carr DB (Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg 2003). 97:1464–1468.
Cichewicz DL, Martin ZL, Smith FL, Welch SP (Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther 1999). 289:859–867.
Cichewicz DL, McCarthy EA (Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther 2003). 304:1010–1015.
Cobos EJ, Portillo-Salido E (“Bedside-to-bench” behavioral outcomes in animal models of pain: beyond the evaluation of reflexes. Curr Neuropharmacol 2013). 11:560–591.
Comer SD, Cooper ZD, Kowalczyk WJ, Sullivan MA, Evans SM, Bisaga AM, Vosburg SK (Evaluation of potential sex differences in the subjective and analgesic effects of morphine in normal, healthy volunteers. Psychopharmacology (Berl) 2010). 208:45–55.
Cook CD, Barrett AC, Roach EL, Bowman JR, Picker MJ (Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the mu opioid receptor. Psychopharmacology (Berl) 2000). 150:430–442.
Cook CD, Nickerson MD (Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund’s adjuvant-induced arthritic male and female rats. J Pharmacol Exp Ther 2005). 313:449–459.
Cooper ZD, Bedi G, Ramesh D, Balter R, Comer SD, Haney M (Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology 2018). 43:2046–2055.
Cooper ZD, Craft RM (Sex-dependent effects of cannabis and cannabinoids: a translational perspective. Neuropsychopharmacology 2018). 43:34–51.
Cox ML, Haller VL, Welch SP (Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol 2007). 567:125–130.
Craft RM (Sex differences in analgesic, reinforcing, discriminative, and motoric effects of opioids. Exp Clin Psychopharmacol 2008). 16:376–385.
Craft RM, Kandasamy R, Davis SM (Sex differences in anti-allodynic, anti-hyperalgesic and anti-edema effects of Δ(9)-tetrahydrocannabinol in the rat. Pain 2013). 154:1709–1717.
De Vita MJ, Moskal D, Maisto SA, Ansell EB (Association of cannabinoid administration with experimental pain in healthy adults: a systematic review and meta-analysis. JAMA Psychiatry 2018). 75:1118–1127.
Dunn KE, Bergeria CL, Huhn AS, Speed TJ, Mun CJ, Vandrey R, Campbell CM (Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model. Neuropsychopharmacology 2021). 46:1451–1459.
Fillingim RB, Ness TJ, Glover TL, Campbell CM, Hastie BA, Price DD, Staud R (Morphine responses and experimental pain: sex differences in side effects and cardiovascular responses but not analgesia. J Pain 2005). 6:116–124.
Finn DP, Beckett SR, Roe CH, Madjd A, Fone KC, Kendall DA, et al. (Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain. Eur J Neurosci 2004). 19:678–686.
Gajtkó A, Bakk E, Hegedűs K, Ducza L, Holló K (IL-1β induced cytokine expression by spinal astrocytes can play a role in the maintenance of chronic inflammatory pain. Front Physiol 2020). 11:543331.
Grenald SA, Young MA, Wang Y, Ossipov MH, Ibrahim MM, Largent-Milnes TM, Vanderah TW (Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology 2017). 116:59–70.
Hargan ED (Determination that a public health Emergency Exists. 2017). https://www.phe.gov/emergency/news/healthactions/phe/Pages/opioids.aspx .
Kazantzis NP, Casey SL, Seow PW, Mitchell VA, Vaughan CW (Opioid and cannabinoid synergy in a mouse neuropathic pain model. Br J Pharmacol 2016). 173:2521–2531.
Keefea FJ, Lefebvrea JC, Egert JR, Affleck G, Sullivand MJ, Caldwell DS (The relationship of gender to pain, pain behavior, and disability in osteoarthritis patients: the role of catastrophizing. Pain 2000). 87:325–334.
Kepler KL, Kest B, Kiefel JM, Cooper ML, Bodnar RJ (Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats. Pharmacol Biochem Behav 1989). 34:119–127.
Kuo A, Wyse BD, Meutermans W, Smith MT ( In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile. Br J Pharmacol 2015). 172:532–548.
Le Foll B (Opioid-sparing effects of cannabinoids: myth or reality? Prog Neuropsychopharmacol Biol Psychiatry 2020). 106:110065.
Lim G, Sung B, Ji RR, Mao J (Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats. Pain 2003). 105:275–283.
Maguire DR, France CP (Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther 2014). 351:383–389.
Maguire DR, France CP (Antinociceptive effects of mixtures of mu opioid receptor agonists and cannabinoid receptor agonists in rats: impact of drug and fixed-dose ratio. Eur J Pharmacol 2018). 819:217–224.
Maguire DR, Yang W, France CP (Interactions between μ-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther 2013). 345:354–362.
Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A, Brenneisen R (The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 2003). 105:79–88.
Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M (Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 2009). 1:1333–1349.
Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, Jamison RN (Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain 2008). 9:254–264.
Nasser SA, Afify EA (Sex differences in pain and opioid mediated antinociception: modulatory role of gonadal hormones. Life Sci 2019). 237:116926.
National Research Council (Guide for the Care and Use of Laboratory Animals: Eighth Edition. 2011). The National Academies Press. p. 201.
Negus SS (Core outcome measures in preclinical assessment of candidate analgesics. Pharmacol Rev 2019). 71:225–266.
Ni J, Gao Y, Gong S, Guo S, Hisamitsu T, Jiang X (Regulation of μ-opioid type 1 receptors by microRNA134 in dorsal root ganglion neurons following peripheral inflammation. Eur J Pain 2013). 17:313–323.
Niesters M, Dahan A, Kest B, Zacny J, Stijnen T, Aarts L, Sarton E (Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain 2010). 151:61–68.
Roberts JD, Gennings C, Shih M (Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur J Pharmacol 2006). 530:54–58.
Rock EM, Limebeer CL, Parker LA (Effect of cannabidiolic acid and Δ9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain. Psychopharmacology (Berl) 2018). 235:3259–3271.
Romero MT, Kepler KL, Bodnar RJ (Gender determinants of opioid mediation of swim analgesia in rats. Pharmacol Biochem Behav 1988). 29:705–709.
Smith FL, Chichewicz D, Martin ZL, Welch SP (The enhancement of morphine antinociception in mice by delta-9-tetrahydrocannabinol. Pharmacol Biochem Behav 1998). 60:559–566.
Stoffel EC, Ulibarri CM, Craft RM (Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats. Pain 2003). 103:285–302.
Sverrisdóttir E, Lund TM, Olesen AE, Drewes AM, Christrup LL, Kreilgaard M (A review of morphine and morphine-6-glucuronide’s pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain. Eur J Pharm Sci 2015). 74:45–62.
Tallarida RJ (Drug synergism: its detection and applications. J Pharmacol Exp Ther 2001). 298:865–872.
Terner JM, Lomas LM, Picker MJ (Influence of estrous cycle and gonadal hormone depletion on nociception and opioid antinociception in female rats of four strains. J Pain 2005). 6:372–383.
Tseng AH, Craft RM (Sex differences in antinociceptive and motoric effects of cannabinoids. Eur J Pharmacol 2001). 430:41–47.
Unruh AM (Gender variations in clinical pain experience. Pain 1996). 65:123–167.
Wang S, Lim G, Mao J, Sung B, Yang L, Mao J (Central glucocorticoid receptors regulate the upregulation of spinal cannabinoid-1 receptors after peripheral nerve injury in rats. Pain 2007). 131:96–105.
Wang X, Traub RJ, Murphy AZ (Persistent pain model reveals sex difference in morphine potency. Am J Physiol Regul Integr Comp Physiol 2006). 291:R300–R306.
Wilson-Poe AR, Pocius E, Herschbach M, Morgan MM (The periaqueductal gray contributes to bidirectional enhancement of antinociception between morphine and cannabinoids. Pharmacol Biochem Behav 2013). 103:444–449.
Wu Y, Yao X, Jiang Y, He X, Shao X, Du J, et al. (Pain aversion and anxiety-like behavior occur at different times during the course of chronic inflammatory pain in rats. J Pain Res 2017). 10:2585–2593.