Effects of Alterations in Cannabinoid Signaling, Alone and in Combination with Morphine, on Pain-Elicited and Pain-Suppressed Behavior in Mice
Open accessAbstract
Inhibitors of fatty acid amide hydrolase (FAAH) and anandamide (AEA) uptake, which limit the degradation of endogenous cannabinoids, have received interest as potential therapeutics for pain. There is also evidence that endogenous cannabinoids mediate the antinociceptive effects of opioids. Assays of pain-elicited and pain-suppressed behavior have been used to differentiate the effects of drugs that specifically alter nociception from drugs that alter nociception caused by nonspecific effects such as catalepsy or a general suppression of activity. Using such procedures, this study examines the effects of the direct cannabinoid type 1 (CB1) agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), the FAAH inhibitor cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), and the AEA uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide (AM404). Additional experiments examined these compounds in combination with morphine. CP55940 produced antinociception in assays of pain-elicited, but not pain-suppressed, behavior and disrupted responding in an assay of schedule-controlled behavior. URB597 and AM404 produced antinociception in assays of pain-elicited and pain-suppressed behavior in which acetic acid was the noxious stimulus, but had no effect on the hotplate and schedule-controlled responding. CP55940 in combination with morphine resulted in effects greater than those of morphine alone in assays of pain-elicited and scheduled-controlled behavior but not pain-suppressed behavior. URB597 in combination with morphine resulted in enhanced morphine effects in assays of pain-elicited and pain-suppressed behavior in which diluted acetic acid was the noxious stimulus, but did not alter morphine's effects on the hotplate or schedule-controlled responding. These studies suggest that, compared with direct CB1 agonists, manipulations of endogenous cannabinoid signaling have enhanced clinical potential; however, their effects depend on the type of noxious stimulus.
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CP55,940 produces a leftward shift of the morphine dose-response curve in the acetic acid abdominal stretching model of visceral pain in mice.
“Additionally, CP55,940 produces a leftward shift of the morphine dose-response curve in the acetic acid abdominal stretching model of visceral pain in mice (Miller et al, 2012).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Miller et al, 2012
Combination of URB597 and morphine produces additive antinociceptive effects in the acetic acid abdominal stretching assay in mice.
“Similarly, combination of URB597 and morphine produces additive antinociceptive effects in the acetic acid abdominal stretching assay and depressed wheel running in mice (Miller et al, 2012).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Miller et al, 2012
Pretreatment with CP55,940 (0.1 mg/kg), a dose ineffective by itself, produces a leftward shift in the dose-response of morphine in the hotplate assay for antinociception.
“In the hotplate assay for antinociception, pretreatment with CP55,940 (0.1 mg/kg), a dose that is ineffective by itself, produces a leftward shift in the dose-response of morphine (Miller et al, 2012).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Miller et al, 2012
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Cites
Guide for the Care and Use of Laboratory Animals: Eighth Edition
(2011) · doi:10.17226/12910 · Cited by 16,199 · see citing works
International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels
Catterall, W. A., Chandy, K. G., Clapham, D. E., Gutman, G. A., Hofmann, F., Harmar, A. J., Abernethy, D. R., & Spedding, M. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.4.5 · Cited by 7,126 · see citing works
International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors
Howlett, A. C., Barth, F., Bonner, T. I., Cabral, G., Casellas, P., Devane, W. A., Felder, C. C., Herkenham, M., Mackie, K., Martin, B. R., et al. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.2.161 · Cited by 2,819 · see citing works
Pertwee, R. G., Howlett, A. C., Abood, M. E., Alexander, S. P. H., Marzo, V. D., Elphick, M. R., Greasley, P. J., Hansen, H. S., Kunos, G., Mackie, K., et al. (2010) · Pharmacological Reviews · doi:10.1124/pr.110.003004 · Cited by 1,610 · see citing works
Cravatt, B. F., Demarest, K., Patricelli, M. P., Bracey, M. H., Giang, D. K., Martin, B. R., & Lichtman, A. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.161191698 · Cited by 1,310 · see citing works
Modulation of anxiety through blockade of anandamide hydrolysis
Kathuria, S., Gaetani, S., Fegley, D., Valiño, F., Duranti, A., Tontini, A., Mor, M., Tarzia, G., Rana, G. L., Calignano, A., et al. (2003) · Nature Medicine · doi:10.1038/nm803 · Cited by 1,293 · see citing works
Institute of Laboratory Animal Resources.
Wolfle, T. L. (1995) · Cited by 620 · see citing works
Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors
Agarwal, N., Pacher, P., Tegeder, I., Amaya, F., Constantin, C. E., Brenner, G. J., Rubino, T., Michalski, C. W., Marsicano, G., Monory, K., et al. (2007) · Nature Neuroscience · doi:10.1038/nn1916 · Cited by 571 · see citing works
Fegley, D., Gaetani, S., Duranti, A., Tontini, A., Mor, M., Tarzia, G., & Piomelli, D. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.078980 · Cited by 427 · see citing works
Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
Clapper, J. R., Moreno-Sanz, G., Russo, R., Guijarro, A., Vacondio, F., Duranti, A., Tontini, A., Sanchini, S., Sciolino, N. R., Spradley, J. M., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2632 · Cited by 346 · cited 2× · see citing works
“In addition, peripheral FAAH inhibition produces CB1-dependent suppression of dorsal horn responses to formalin injection in the hind paw of rats (Clapper et al., 2010).”
BackgroundBlockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain
Kinsey, S. G., Long, J. Z., O’Neal, S. T., Abdullah, R. A., Poklis, J. L., Boger, D. L., Cravatt, B. F., & Lichtman, A. H. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.155465 · Cited by 330 · see citing works
Lichtman, A. H., Leung, D., Shelton, C. C., Saghatelian, A., Hardouin, C., Boger, D. L., & Cravatt, B. F. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.069401 · Cited by 329 · see citing works
Lichtman, A. H., Shelton, C. C., Advani, T., & Cravatt, B. F. (2004) · Pain · doi:10.1016/j.pain.2004.01.022 · Cited by 301 · see citing works
Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models
Jayamanne, A., Greenwood, R., Mitchell, V. A., Aslan, S., Piomelli, D., & Vaughan, C. W. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706510 · Cited by 287 · see citing works
Preclinical Assessment of Candidate Analgesic Drugs: Recent Advances and Future Challenges
Negus, S. S., Vanderah, T. W., Brandt, M. R., Bilsky, E. J., Becerra, L. R., & Borsook, D. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.106377 · Cited by 255 · see citing works
Fegley, D., Kathuria, S., Mercier, R., Li, C., Goutopoulos, A., Makriyannis, A., & Piomelli, D. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400997101 · Cited by 230 · see citing works
Welch, S. P., & Stevens, D. L. (1992) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)10720-9 · Cited by 208 · see citing works
Mitrirattanakul, S., Ramakul, N., Guerrero, A. V., Matsuka, Y., Ono, T., Iwase, H., Mackie, K., Faull, K. F., & Spigelman, I. (2006) · Pain · doi:10.1016/j.pain.2006.06.016 · Cited by 207 · see citing works
Clement, A. B., Hawkins, E. G., Lichtman, A. H., & Cravatt, B. F. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-09-03916.2003 · Cited by 187 · see citing works
Russo, R., LoVerme, J., La Rana, G., Compton, T. R., Parrott, J., Duranti, A., Tontini, A., Mor, M., Tarzia, G., Calignano, A., et al. (2007) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.119941 · Cited by 182 · see citing works
Identification of a high-affinity binding site involved in the transport of endocannabinoids
Moore, S. A., Nomikos, G. G., Chesterfield, A. K., Schober, D. A., Schaus, J. M., Ying, B.-P., Xu, Y., Phebus, L. A., Simmons, R. M. A., Li, D., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507470102 · Cited by 164 · see citing works
Antinociceptive Synergy between Δ9-Tetrahydrocannabinol and Opioids after Oral Administration
Cichewicz, D. L., & McCarthy, E. A. (2003) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.045575 · Cited by 154 · see citing works
Interactions between delta 9-tetrahydrocannabinol and kappa opioids in mice.
Smith, P. B., Welch, S. P., & Martin, B. R. (1994) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)38633-7 · Cited by 131 · see citing works
Welch, S. P., Thomas, C., & Patrick, G. (1995) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)24328-2 · Cited by 124 · see citing works
A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats
Pascual, D., Goicoechea, C., Suardíaz, M., & Martín, M. I. (2005) · Pain · doi:10.1016/j.pain.2005.07.008 · Cited by 117 · see citing works
Booker, L., Kinsey, S. G., Abdullah, R. A., Blankman, J. L., Long, J. Z., Ezzili, C., Boger, D. L., Cravatt, B. F., & Lichtman, A. H. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01445.x · Cited by 116 · see citing works
Stevenson, G. W., Bilsky, E. J., & Negus, S. S. (2006) · Journal of Pain · doi:10.1016/j.jpain.2006.01.447 · Cited by 105 · see citing works
Costa, B., Siniscalco, D., Trovato, A. E., Comelli, F., Sotgiu, M. L., Colleoni, M., Maione, S., Rossi, F., & Giagnoni, G. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706798 · Cited by 99 · see citing works
Solinas, M., Panlilio, L. V., Tanda, G., Makriyannis, A., Matthews, S. A., & Goldberg, S. R. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300754 · Cited by 96 · see citing works
Interaction of the cannabinoid and opioid systems in the modulation of nociception
Welch, S. P. (2009) · International Review of Psychiatry · doi:10.1080/09540260902782794 · Cited by 92 · see citing works
Spinal mechanisms ofΔ9-tetrahydrocannabinol-induced analgesia
Smith, P. B., & Martin, B. R. (1992) · Brain Research · doi:10.1016/0006-8993(92)90222-u · Cited by 91 · see citing works
Carmo, G. P. D., Stevenson, G. W., Carlezon, W. A., & Negus, S. S. (2009) · Pain · doi:10.1016/j.pain.2009.04.010 · Cited by 88 · see citing works
Justinová, Z., Munzar, P., Panlilio, L. V., Yaşar, S., Redhi, G. H., Tanda, G., & Goldberg, S. R. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.21 · Cited by 86 · see citing works
Da Fonseca Pacheco, D., Klein, A., De Castro Perez, A., Da Fonseca Pacheco, C. M., De Francischi, J. N., & Duarte, I. D. G. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.175 · Cited by 81 · see citing works
Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat
Cox, M. L., Haller, V. L., & Welch, S. P. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.04.010 · Cited by 78 · see citing works
Finn, D. P., Beckett, S. R. G., Roe, C. H., Madjd, A., Fone, K. C. F., Kendall, D. A., Marsden, C. A., & Chapman, V. (2004) · European Journal of Neuroscience · doi:10.1111/j.0953-816x.2004.03177.x · Cited by 76 · see citing works
Adermark, L., & Lovinger, D. M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3842-08.2009 · Cited by 71 · see citing works
Negus, S. S., & Rice, K. C. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2008.127 · Cited by 70 · see citing works
Pacheco, D. D. F., Klein, A., Perez, A. C., Pacheco, C. M. D. F., Francischi, J. N., Reis, G. M. L., & Duarte, I. D. G. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00310.x · Cited by 68 · see citing works
Cannabinoid agonist-induced sensitisation to morphine place preference in mice
Manzanedo, C., Aguilar, M. A., Rodríguez‐Arias, M., Navarro, M. A., & Miñarro, J. (2004) · Neuroreport · doi:10.1097/01.wnr.0000126217.87116.8c · Cited by 67 · see citing works
Costa, B., Bettoni, I., Petrosino, S., Comelli, F., Giagnoni, G., & Di Marzo, V. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.02.001 · Cited by 64 · see citing works
Norwood, C. S., Cornish, J. L., Mallet, P. E., & McGregor, I. S. (2003) · European Journal of Pharmacology · doi:10.1016/s0014-2999(03)01455-9 · Cited by 63 · see citing works
Stevenson, G. W., Cormier, J., Mercer, H., Adams, C., Dunbar, C., Negus, S. S., & Bilsky, E. J. (2009) · Life Sciences · doi:10.1016/j.lfs.2009.06.006 · Cited by 63 · see citing works
Massi, P., Vaccani, A., Romorini, S., & Parolaro, D. (2001) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(01)00323-x · Cited by 54 · see citing works
Diaz, S. V., Farhang, B., Hoien, J., Stahlman, M., Adatia, N., Cox, J. M., & Wagner, E. J. (2009) · Neuroendocrinology · doi:10.1159/000191646 · Cited by 50 · see citing works
Modulation of opioids via protection of anandamide degradation by fatty acid amide hydrolase
Haller, V. L., Stevens, D. L., & Welch, S. P. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.08.005 · Cited by 45 · see citing works
rbe, T. U. C. J., & DiPatrizio, N. V. (2005) · Behavioural Pharmacology · doi:10.1097/00008877-200509000-00009 · Cited by 45 · see citing works
Smith, M. A., Naples, J. G., Lyle, M. A., Iordanou, J. C., & Felder, J. N. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.150011 · Cited by 38 · see citing works
Effects of morphine on pain-elicited and pain-suppressed behavior in CB1 knockout and wildtype mice
Miller, L. L., Picker, M. J., Schmidt, K. T., & Dykstra, L. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2232-5 · Cited by 35 · see citing works
Self-citationNeuropeptide FF receptors antagonist, RF9, attenuates opioid-evoked hypothermia in mice
Wang, Y., Guo, J., Wang, S.-B., Fang, Q., He, F., & Wang, R. (2008) · Peptides · doi:10.1016/j.peptides.2008.02.016 · Cited by 26 · see citing works
Li, D., Olszewski, P. K., Shi, Q., Grace, M. K., Billington, C. J., Kotz, C. M., & Levine, A. S. (2006) · Brain Research · doi:10.1016/j.brainres.2006.04.031 · Cited by 24 · see citing works
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Wilkerson, J. L., Ghosh, S., Mustafa, M., Abdullah, R. A., Niphakis, M. J., Cabrera, R., Maldonado, R. L., Cravatt, B. F., & Lichtman, A. H. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.11.015 · Cited by 78 · see citing works
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- Authors
- Miller, L. L., Picker, M. J., Umberger, M. D., Schmidt, K. T., & Dykstra, L. A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 342
- Issue
- 1
- Pages
- 177-187
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC3383037
- OpenAlex
- W2166159921
- Cited by
- 44
- References
- 51
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 9 · 2014: 3 · 2013: 3
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (DA007244)
- National Institute on Drug Abuse (F31DA025446, R01DA002749, T32DA007244)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- endocannabinoid system, cannabinoid signaling, morphine, antinociception, CB1 receptor agonists, CP55,940, URB597, fatty acid amide hydrolase inhibitors, AM404, opioid-cannabinoid interaction, acetic acid-induced writhing, schedule-controlled behavior, hot plate test, analgesic drug development
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Analgesics, Animals, Arachidonic Acids, Benzamides, Carbamates, Cyclohexanols, Male, Mice, Inbred C57BL, Morphine, Pain, Receptor, Cannabinoid, CB1, Mice, Polyunsaturated Alkamides, Nociception, Cannabinoid Receptor Modulators, Endocannabinoids
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