Abstract
Rationale and objectives
Pain sensation can negatively impact cognitive function, including impulsivity. Pain-induced changes in impulsivity can contribute to development of psychiatric comorbidities found in those with chronic pain conditions. The goal of this study was to determine whether complete Freund’s adjuvant (CFA)-induced pain manipulation enhances impulsivity in rats. Whether the pain-induced impulsivity is sexually dimorphic, and if mu-opioid receptors play a role in these processes.
Methods
Male and female rats were screened for trait impulsivity and designated as high or low impulsive using a delay discounting task. Rats then received a hind paw injection of CFA, and their impulsivity was assessed for 16 days. The effects of morphine on impulsivity were also examined. In a separate experiment, rats were pretreated with beta-funaltrexamine (β-FNA) to determine the role of mu-opioid receptors on impulsivity.
Results
CFA treatment increased impulsivity in males and females. The onset of CFA-induced impulsivity was faster in high impulsive females than males. Morphine blocked CFA-induced impulsivity in both sexes in a dose- and time-dependent manner. β-FNA prevented the actions of morphine on CFA-induced impulsivity in high impulsive males, but not high impulsive females. Moreover, β-FNA increased CFA-induced impulsivity in morphine naïve males, but not females.
Conclusion
These findings demonstrate unique sex differences in CFA-induced impulsivity, response to morphine, and the impact of mu-opioid receptors. A better understanding of cognitive deficits and their mechanisms can provide insight into the development of substance abuse and psychiatric comorbidities that occur in people with chronic pain.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adams WK, Levesque DL, Cocker PJ et al (2020) Decreased motor impulsivity following chronic lithium treatment in male rats is associated with reduced levels of pro-inflammatory cytokines in the orbitofrontal cortex. Brain Behav Immun 89:339–349. https://doi.org/10.1016/j.bbi.2020.07.018
Altarifi AA, Negus SS (2015) Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats. Eur J Pharmacol 748:76–82. https://doi.org/10.1016/j.ejphar.2014.12.011
Andrade LF, Alessi SM, Petry NM (2013) The Effects of Alcohol Problems and Smoking on Delay Discounting in Individuals with Gambling Problems. J Psychoactive Drugs 45:241–248. https://doi.org/10.1080/02791072.2013.803645
Apkarian AV, Sosa Y, Krauss BR et al (2004) Chronic pain patients are impaired on an emotional decision-making task. Pain 108:129–136. https://doi.org/10.1016/j.pain.2003.12.015
Armendariz A, Nazarian A (2018) Morphine antinociception on thermal sensitivity and place conditioning in male and female rats treated with intraplantar complete freund’s adjuvant. Behav Brain Res 343:21–27. https://doi.org/10.1016/j.bbr.2018.01.031
Bagley EE, Ingram SL (2020) Endogenous opioid peptides in the descending pain modulatory circuit. Neuropharmacology 173:108131. https://doi.org/10.1016/j.neuropharm.2020.108131
Chakrabarti S, Liu N-J, Gintzler AR (2010) Formation of mu-/kappa-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia. Proc Natl Acad Sci U S A 107:20115–20119. https://doi.org/10.1073/pnas.1009923107
Chefer VI, Denoroy L, Zapata A, Shippenberg TS (2009) Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanisms. Eur J Neurosci 30:272–278. https://doi.org/10.1111/j.1460-9568.2009.06827.x
Chen W, Marvizón JC (2020) A Src family kinase maintains latent sensitization in rats, a model of inflammatory and neuropathic pain. Brain Res 1746:146999. https://doi.org/10.1016/j.brainres.2020.146999
Cicero TJ, Lynskey M, Todorov A et al (2008) Co-morbid pain and psychopathology in males and females admitted to treatment for opioid analgesic abuse. Pain 139:127–135. https://doi.org/10.1016/j.pain.2008.03.021
Corder G, Castro DC, Bruchas MR, Scherrer G (2018) Endogenous and exogenous opioids in pain. Annu Rev Neurosci 41:453–473. https://doi.org/10.1146/annurev-neuro-080317-061522
Corder G, Doolen S, Donahue RR et al (2013) Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science 341:1394–1399. https://doi.org/10.1126/science.1239403
Coy TR, Kanarek RB (2006) Chronic sucrose intake reduces the antagonist effect of β-funaltrexamine on morphine-induced antinociception in female but not in male rats. Nutr Neurosci 9:131–139. https://doi.org/10.1080/10284150600895881
Craft RM, Mogil JS, Aloisi AM (2004) Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain 8:397–411. https://doi.org/10.1016/j.ejpain.2004.01.003
Cui GB, Jia-ze A, Nan Z, Zhao MG, Liu SB, Yi J et al (2012) Elevated interleukin-8 enhances prefrontal synaptic transmission in mice with persistent inflammatory pain. Mol Pain 8:11. https://doi.org/10.1186/1744-8069-8-11
Cunha AM, Esteves M, Pereira-Mendes J et al (2020) High trait impulsivity potentiates the effects of chronic pain on impulsive behavior. Neurobiol Pain 7:100042. https://doi.org/10.1016/j.ynpai.2019.100042
Eppolito AK, France CP, Gerak LR (2013) Effects of acute and chronic morphine on delay discounting in pigeons. J Exp Anal Behav 99:277–289. https://doi.org/10.1002/jeab.25
Evenden JL (1999) Varieties of impulsivity. Psychopharmacol 146:348–361. https://doi.org/10.1007/PL00005481
Fox AT, Hand DJ, Reilly MP (2008) Impulsive choice in a rodent model of attention-deficit/hyperactivity disorder. Behav Brain Res 187:146–152. https://doi.org/10.1016/j.bbr.2007.09.008
Gan JO, Walton ME, Phillips PEM (2010) Dissociable cost and benefit encoding of future rewards by mesolimbic dopamine. Nat Neurosci 13:25–27. https://doi.org/10.1038/nn.2460
Gee TA, Weintraub NC, Lu D et al (2020) A pain-induced tonic hypodopaminergic state augments phasic dopamine release in the nucleus accumbens. Pain Publish Ah. https://doi.org/10.1097/j.pain.0000000000001925
Gouardères C, Jhamandas K, Sutak M, Zajac JM (1996) Role of opioid receptors in the spinal antinociceptive effects of neuropeptide FF analogues. Br J Pharmacol 117:493–501. https://doi.org/10.1111/j.1476-5381.1996.tb15217.x
Harton LR, Richardson JR, Armendariz A, Nazarian A (2017) Dissociation of morphine analgesic effects in the sensory and affective components of formalin-induced spontaneous pain in male and female rats. Brain Res 1658:36–41. https://doi.org/10.1016/j.brainres.2017.01.011
Hipólito L, Wilson-Poe A, Campos-Jurado Y et al (2015) Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors. J Neurosci 35:12217–12231. https://doi.org/10.1523/jneurosci.1053-15.2015
Íbias J, Nazarian A (2020) Sex differences in nicotine-induced impulsivity and its reversal with bupropion in rats. J Psychopharmacol 34:1382–1392. https://doi.org/10.1177/0269881120937543
Ji G, Sun H, Fu Y et al (2010) Cognitive Impairment in Pain through Amygdala-Driven Prefrontal Cortical Deactivation. J Neurosci 30:5451–5464. https://doi.org/10.1523/JNEUROSCI.0225-10.2010
Jia D, Gao GD, Liu Y et al (2007) TNF-α involves in altered prefrontal synaptic transmission in mice with persistent inflammatory pain. Neurosci Lett 415:1–5. https://doi.org/10.1016/j.neulet.2006.12.032
Kest B, Sarton E, Dahan A (2000) Gender differences in opioid-mediated analgesia: animal and human studies. Anesthesiol 93:539–547
Kieres AK, Hausknecht KA, Farrar AM et al (2004) Effects of morphine and naltrexone on impulsive decision making in rats. Psychopharmacol 173:167–174. https://doi.org/10.1007/s00213-003-1697-2
Kirby KN, Petry NM (2004) Heroin and cocaine abusers have higher discount rates for delayed rewards than alcoholics or non-drug-using controls. Addiction 99:461–471. https://doi.org/10.1111/j.1360-0443.2003.00669.x
Koot S, van den Bos R, Adriani W, Laviola G (2009) Gender differences in delay-discounting under mild food restriction. Behav Brain Res 200:134–143. https://doi.org/10.1016/j.bbr.2009.01.006
Laredo SA, Steinman MQ, Robles CF et al (2015) Effects of defeat stress on behavioral flexibility in males and females: Modulation by the mu-opioid receptor. Eur J Neurosci 41:434–441. https://doi.org/10.1111/ejn.12824
Legakis LP, Negus SS (2018) Repeated Morphine Produces Sensitization to Reward and Tolerance to Antiallodynia in Male and Female Rats with Chemotherapy-Induced Neuropathy. J Pharmacol Exp Ther 365:9–19. https://doi.org/10.1124/jpet.117.246215
Leitl MD, Onvani S, Bowers MS et al (2014) Pain-related depression of the mesolimbic dopamine system in rats: Expression, blockade by analgesics, and role of endogenous κ-opioids. Neuropsychopharmacol 39:614–624. https://doi.org/10.1038/npp.2013.236
Liu JG, Ruckle MB, Prather PL (2001) Constitutively Active μ-Opioid Receptors Inhibit Adenylyl Cyclase Activity in Intact Cells and Activate G-proteins Differently than the Agonist [D-Ala2, N-MePhe4, Gly-ol5]Enkephalin. J Biol Chem 276:37779–37786. https://doi.org/10.1074/jbc.M106104200
Liu N, Von GH, Gintzler AR (2007) Sexually Dimorphic Recruitment of Spinal Opioid Analgesic Pathways by the Spinal Application of Morphine. J Pharmacol Exp Ther. 322:654–660. https://doi.org/10.1124/jpet.107.123620.system
Maguire DR, Gerak LR, France CP (2016) Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Behav Pharmacol 27:155–164. https://doi.org/10.1097/FBP.0000000000000194
Maguire DR, Li JX, France CP (2012) Impulsivity and drugs of abuse: A juice-reinforced operant procedure for determining within-session delay discounting functions in rhesus monkeys. J Pharmacol Toxicol Methods 66:264–269. https://doi.org/10.1016/j.vascn.2012.08.168
Martin TJ, Buechler NL, Kim SA et al (2011) Involvement of the lateral amygdala in the antiallodynic and reinforcing effects of heroin in rats after peripheral nerve injury. Anesthesiol 114:633–642. https://doi.org/10.1097/ALN.0b013e318209aba7
Marx I, Hacker T, Yu X et al (2018) ADHD and the Choice of Small Immediate Over Larger Delayed Rewards: A Comparative Meta-Analysis of Performance on Simple Choice-Delay and Temporal Discounting Paradigms. J Atten Disord 25:171–187. https://doi.org/10.1177/1087054718772138
Mazur JE (1987) An adjusting procedure for studying delayed reinforcement. In: Commons ML, Mazur JE, Nevin JA, Rachlin H (eds) Quantitative Analysis of Behavior, vol 5. First. Psychology Press- Taylor & Francis, New Jersey, pp 55–76
Meye FJ, Ramakers GMJ, Adan RAH (2014) The vital role of constitutive GPCR activity in the mesolimbic dopamine system. Transl Psychiatry 4:1–8. https://doi.org/10.1038/tp.2013.130
Meye FJ, van Zessen R, Smidt MP et al (2012) Morphine withdrawal enhances constitutive μ-opioid receptor activity in the ventral tegmental area. J Neurosci 32:16120–16128. https://doi.org/10.1523/JNEUROSCI.1572-12.2012
Michot B, Bourgoin S, Viguier F et al (2012) Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat. Pain 153:1939–1948. https://doi.org/10.1016/j.pain.2012.06.009
Miller LR, Cano A (2009) Comorbid chronic pain and depression: who is at risk? J Pain 10:619–627. https://doi.org/10.1016/j.jpain.2008.12.007
Moeller FG, Barratt ES, Ph D et al (2001) Reviews and Overviews Psychiatric Aspects of Impulsivity. Psychiatry Interpers Biol Process 158:1783–1793. https://doi.org/10.1111/j.1467-789X.2011.00899.x
Mora S, Martín-González E, Prados-Pardo Á et al (2020) Increased vulnerability to impulsive behavior after streptococcal antigen exposure and antibiotic treatment in rats. Brain Behav Immun 89:675–688. https://doi.org/10.1016/j.bbi.2020.08.010
Mora S, Martín-González E, Prados-Pardo Á, et al (2021) Increased compulsivity in adulthood after early adolescence immune activation: Preclinical evidence. Int J Environ Res Public Health 18:4684. https://doi.org/10.3390/ijerph18094684
Moschak TM, Carelli RM (2017) Impulsive rats exhibit blunted dopamine release dynamics during a delay discounting task independent of cocaine history. Eneuro 4:ENEURO.0119–17.2017. https://doi.org/10.1523/ENEURO.0119-17.2017
Ossipov MH, Kovelowski CJ, Wheeler-Aceto H et al (1996) Opioid antagonists and antisera to endogenous opioids increase the nociceptive response to formalin: Demonstration of an opioid kappa and delta inhibitory tone. J Pharmacol Exp Ther 277:784–788
Ozaki S, Narita M, Narita M et al (2002) Suppression of the morphine-induced rewarding effect in the rat with neuropathic pain: implication of the reduction in mu-opioid receptor functions in the ventral tegmental area. J Neurochem 82:1192–1198
Pais-Vieira M, Mendes-Pinto MM, Lima D, Galhardo V (2009) Cognitive impairment of prefrontal-dependent decision-making in rats after the onset of chronic pain. Neurosci 161:671–679. https://doi.org/10.1016/j.neuroscience.2009.04.011
Pattij T, Schetters D, Janssen MCW et al (2009) Acute effects of morphine on distinct forms of impulsive behavior in rats. Psychopharmacol 205:489–502. https://doi.org/10.1007/s00213-009-1558-8
Perry JL, Nelson SE, Anderson MM et al (2007) Impulsivity (delay discounting) for food and cocaine in male and female rats selectively bred for high and low saccharin intake. Pharmacol Biochem Behav 86:822–837. https://doi.org/10.1016/j.pbb.2007.03.012
Pitcher GM, Ritchie J, Henry JL (1999) Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands. J Neurosci Methods 87:185–193. https://doi.org/10.1016/s0165-0270(99)00004-7
Ren W, Centeno MV, Berger S et al (2016) The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain. Nat Neurosci 19:220–222. https://doi.org/10.1038/nn.4199
Rutten K, De Vry J, Robens A et al (2011) Dissociation of rewarding, anti-aversive and anti-nociceptive effects of different classes of anti-nociceptives in the rat. Eur J Pain 15:299–305. https://doi.org/10.1016/j.ejpain.2010.07.011
Saddoris MP, Sugam JA, Stuber GD et al (2015) Mesolimbic Dopamine Dynamically Tracks, and Is Causally Linked to, Discrete Aspects of Value-Based Decision Making. Biol Psychiatry 77:903–911. https://doi.org/10.1016/j.biopsych.2014.10.024
Schäfer M, Imai Y, Uhl GR, Stein C (1995) Inflammation enhances peripheral μ-opioid receptor-mediated analgesia, but not μ-opioid receptor transcription in dorsal root ganglia. Eur J Pharmacol 279:165–169. https://doi.org/10.1016/0014-2999(95)00150-J
Taylor AMW, Castonguay A, Taylor AJ et al (2015) Microglia disrupt mesolimbic reward circuitry in chronic pain. J Neurosci 35:8442–8450. https://doi.org/10.1523/JNEUROSCI.4036-14.2015
Tompkins DA, Johnson PS, Smith MT et al (2016) Temporal preference in individuals reporting chronic pain: discounting of delayed pain-related and monetary outcomes. Pain 157:1724–1732. https://doi.org/10.1097/j.pain.0000000000000576
van der Kam EL, Vry JD, Schiene K, Tzschentke TM (2008) Differential effects of morphine on the affective and the sensory component of carrageenan-induced nociception in the rat. Pain 136:373–379. https://doi.org/10.1016/j.pain.2007.07.027
Van Haaren F, Van Hest A, Van De Poll NE (1988) Self-control in male and female rats. J Exp Anal Behav 49:201–211. https://doi.org/10.1901/jeab.1988.49-201
Verdejo-García A, López-Torrecillas F, Calandre EP et al (2009) Executive function and decision-making in women with fibromyalgia. Arch Clin Neuropsychol 24:113–122. https://doi.org/10.1093/arclin/acp014
Vonder Haar C, Martens KM, Riparip LK et al (2017) Frontal Traumatic Brain Injury Increases Impulsive Decision Making in Rats: A Potential Role for the Inflammatory Cytokine Interleukin-12. J Neurotrauma 34:2790–2800. https://doi.org/10.1089/neu.2016.4813
Wakaizumi K, Jabakhanji R, Ihara N et al (2019) Altered functional connectivity associated with time discounting in chronic pain. Sci Rep 9:1–11. https://doi.org/10.1038/s41598-019-44497-5
Walteros C, Sánchez-Navarro JP, Muñoz MA et al (2011) Altered associative learning and emotional decision making in fibromyalgia. J Psychosom Res 70:294–301. https://doi.org/10.1016/j.jpsychores.2010.07.013
Wang X, Traub RJ, Murphy AZ (2006) Persistent pain model reveals sex difference in morphine potency. Am J Physiol Regul Integr Comp Physiol 291:R300–R306. https://doi.org/10.1152/ajpregu.00022.2006
Wiech K, Tracey I (2009) The influence of negative emotions on pain: behavioral effects and neural mechanisms. Neuroimage 47:987–994. https://doi.org/10.1016/j.neuroimage.2009.05.059
Winstanley CA, Theobald DEH, Cardinal RN, Robbins TW (2004) Contrasting roles of basolateral amygdala and orbitofrontal cortex in impulsive choice. J Neurosci 24:4718–4722. https://doi.org/10.1523/JNEUROSCI.5606-03.2004
Xiao L, Becker JB (1998) Effects of estrogen agonists on amphetamine-stimulated striatal dopamine release. Synapse 29:379–391. https://doi.org/10.1002/(SICI)1098-2396(199808)29:4%3c379::AID-SYN10%3e3.0.CO;2-M
Acknowledgements
This work was made possible by funds provided by the Western University of Health Sciences. The authors declare no conflict of interests.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Nidia Espinoza Serrano and Samuel G. Saputra have equally contributed to the manuscript
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Serrano, N.E., Saputra, S.G., Íbias, J. et al. Pain-induced impulsivity is sexually dimorphic and mu-opioid receptor sensitive in rats. Psychopharmacology 238, 3447–3462 (2021). https://doi.org/10.1007/s00213-021-05963-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-021-05963-z