Many injuries cause pain and inflammation, which are one of the major challenges for physicians. In this study, the analgesic and the anti-inflammatory effects of milnacipran were investigated on carrageenan-induced nociception and inflammation in male rats.
Pain and inflammation were induced by injection of λ-carrageenan (1% v/v) into the hind paw. Indomethacin (10 mg/kg: ip) or milnacipran (10, 20 and 40 mg/kg: ip) were administered 30 min before carrageenan. Analgesia and inflammation were measured by hot plate and plethysmometer. Finally, lipid peroxidation, tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), myeloperoxidase (MPO) activity, nitric oxide (NO) and total antioxidant capacity (TAC) status evaluated in the hind paw tissue.
The results showed that carrageenan caused hyperalgesia and inflammation in the hind paw tissue. Milnacipran (20 and 40 mg/kg) significantly and dose-dependently attenuated (65 ± 3.2%; p ≤0.01 and 42 ± 6.2%; p ≤ 0.001, respectively) carrageenan-induced inflammation and significantly increased (p ≤ 0.001) nociception threshold. Also, milnacipran (20 and 40 mg/kg) significantly suppressed levels of malondialdehyde (MDA), NO (p ≤ 0.05), MPO activity, TNF-α, IL-1β and IL-6 (p ≤ 0.001) following carrageenan injection. Additionally, milnacipran (10, 20 and 40 mg/kg) significantly augmented (p ≤ 0.05) TAC status following carrageenan in the hind paw tissue.
In the present study, milnacipran showed anti-nociceptive and anti-inflammatory effects on carrageenan-induced hyperalgesia and inflammation in a dose-dependent manner. Milnacipran reduced inflammatory edema and increased the paw withdrawal threshold probably through suppression of MDA, NO, TNF-α, IL-1β, IL-6 and MPO activity, and increase of TAC status in the hind paw tissue. Therefore, milnacipran holds important potential as an anti-inflammatory and anti-nociceptive drug. Although, further clinical trials to confirm this issue, is required.
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Bach-Rojecky L, Lackovic Z (2005) Antinociceptive effect of botulinum toxin type a in rat model of carrageenan and capsaicin induced pain. Croat Med J 46:201–208
Bavill J (1997) Mechanisms of action of opioid and non-steroidal antiœinflammatory drug. Eur J Anesthesiol 14:9
Berrocoso E, Mico J-A, Vitton O, Ladure P, Newman-Tancredi A, Depoortère R, Bardin L (2011) Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain. Euro J Pharmacol 655:46–51
Bilici D, Akpinar E, Kiziltunc A (2002) Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharmacolog Res 46:133–139
Brune K, Patrignani P (2015) New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res 8:105
Buritova J, Honoré P, Besson J-M (1995) Indomethacin reduces both Krox-24 expression in the rat lumbar spinal cord and inflammatory signs following intraplantar carrageenan. Brain Res 674:211–220
Derry S, Gill D, Phillips T, Moore RA (2012) Milnacipran for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 3(3):CD008244
Dharmshaktu P, Tayal V, Kalra BS (2012) Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol 52:6–17
Fröde TS, Medeiros Y (2001) Myeloperoxidase and adenosine-deaminase levels in the pleural fluid leakage induced by carrageenan in the mouse model of pleurisy. Mediators Inflamm 10:223–227
Guay J, Bateman K, Gordon R, Mancini J, Riendeau D (2004) Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of microsomal PGE2 synthase-1. J Biol Chem 279:24866–24872
Haddadi R, Nayebi AM, Brooshghalan SE (2018a) Silymarin prevents apoptosis through inhibiting the bax/caspase-3 expression and suppresses toll like receptor-4 pathway in the SNc of 6-OHDA intoxicated rats. Biomed Pharmacother 104:127–136
Haddadi R, Poursina M, Zeraati F, Nadi F (2018b) Gastrodin microinjection suppresses 6-OHDA-induced motor impairments in parkinsonian rats: insights into oxidative balance and microglial activation in SNc Inflammopharmacology. Inflammopharmacology 26(5):1305–1316
Hammody LE, Matloub SY, Shihab SS (2015) Pregabalin versus amitriptyline in the treatment of fibromyalgia patients (a double blind comparative study). Iraqi Acad Sci J 14:38–44
Handy RL, Moore PK (1998) Effects of selective inhibitors of neuronal nitric oxide synthase on carrageenan-induced mechanical and thermal hyperalgesia. Neuropharmacology 37:37–43
Hosseini A, Abdollahi M (2013) Diabetic neuropathy and oxidative stress: therapeutic perspectives oxidative medicine and cellular longevity 2013:168039
Hwang H-J, Lee H-J, Kim C-J, Shim I, Hahm D-H (2008) Inhibitory effect of amygdalin on lipopolysaccharide-inducible TNF-alpha and IL-1beta mRNA expression and carrageenan-induced rat arthritis. J Microbiol Biotechnol 18:1641–1647
Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E (2012) Evidence of central inflammation in fibromyalgia—increased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol 242:33–38
Khattab MM (2006) TEMPOL, a membrane-permeable radical scavenger, attenuates peroxynitrite-and superoxide anion-enhanced carrageenan-induced paw edema and hyperalgesia: a key role for superoxide anion. Euro J Pharmacol 548:167–173
Kheradmand A, Mohajjel Nayebi A, Jorjani M, Haddadi R (2016a) Effect of WR-1065 on 6-hydroxydopamine-induced catalepsy and IL-6 level in rats. Iran J Basic Med Sci 19:490–496
Kheradmand A, Nayebi AM, Jorjani M, Khalifeh S, Haddadi R (2016b) Effects of WR1065 on 6-hydroxydopamine-induced motor imbalance: possible involvement of oxidative stress and inflammatory cytokines. Neurosci Lett 627:7–12. https://doi.org/10.1016/j.neulet.2016.05.040
King T, Rao S, Vanderah T, Chen Q, Vardanyan A, Porreca F (2006) Differential blockade of nerve injury-induced shift in weight bearing and thermal and tactile hypersensitivity by milnacipran. J Pain 7:513–520
Littlejohn G, Guymer E (2018) Neurogenic inflammation in fibromyalgia. Seminars in immunopathology, vol 3. Springer, Berlin, pp 291–300
Luedde T, Schwabe RF (2011) NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 8:108
Menendez L, Lastra A, Hidalgo A, Baamonde A (2002) Unilateral hot plate test: a simple and sensitive method for detecting central and peripheral hyperalgesia in mice. J Neurosci Methods 113:91–97
Mico JA, Berrocoso E, Vitton O, Ladure P, Newman-Tancredi A, Bardin L, Depoortère R (2011) Effects of milnacipran, duloxetine and indomethacin, in polyarthritic rats using the Randall–Selitto model. Behav Pharmacol 22:599–606
Mizokami SS et al (2016) Pimaradienoic acid inhibits carrageenan-induced inflammatory leukocyte recruitment and edema in mice: inhibition of oxidative stress, nitric oxide and cytokine production. PLoS ONE 11:e0149656
Morris CJ (2003) Carrageenan-induced paw edema in the rat and mouse. Inflammation protocols. Springer, Berlin, pp 115–121
Namgyal D, Sarwat M (2020) Saffron as a neuroprotective agent. Saffron. Elsevier, Netherlands, pp 93–102
Neeb L, Hellen P, Boehnke C, Hoffmann J, Schuh-Hofer S, Dirnagl U, Reuter U (2011) IL-1β stimulates COX-2 dependent PGE2 synthesis and CGRP release in rat trigeminal ganglia cells. PLoS ONE 6(3):e17360
Rafiee L, Hajhashemi V, Javanmard SH (2017) In vitro and in vivo modulation of LPS and carrageenan-induced expression of inflammatory genes by amitriptyline. J Pharm Pharmacog Res 5:144–155
Rao P, Knaus EE (2008) Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharmaceut Sci 11:81–110
Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y (2014) Fibromyalgia and cytokines. Immunol Lett 161:200–203
Ruiz-Miyazawa KW, Zarpelon AC, Pinho-Ribeiro FA, Pavão-de-Souza GF, Casagrande R, Verri WA Jr (2015) Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-κB activation in the paw and spinal cord. PLoS ONE 10:e0118942
Sammons MJ, Raval P, Davey PT, Rogers D, Parsons AA, Bingham S (2000) Carrageenan-induced thermal hyperalgesia in the mouse: role of nerve growth factor and the mitogen-activated protein kinase pathway. Brain Res 876:48–54
Sayyah M, Mandgary A, Kamalinejad M (2002) Evaluation of the anticonvulsant activity of the seed acetone extract of Ferula gummosa Boiss. against seizures induced by pentylenetetrazole and electroconvulsive shock in mice. J Ethnopharmacol 82:105–109
Schug SA, Zech D, Grond S (1992) Adverse effects of systemic opioid analgesics. Drug Saf 7:200–213
Sharma B, Kumar H, Kaushik P, Mirza R, Awasthi R, Kulkarni G (2020) Therapeutic benefits of saffron in brain diseases: new lights on possible pharmacological mechanisms. Saffron. Elsevier, Netherlands, pp 117–130
Stejskal V, Öckert K, Bjørklund G (2013) Metal-induced inflammation triggers fibromyalgia in metal-allergic patients. Neuroendocrinol Lett 34:559–565
Suarez-Roca H, Quintero L, Arcaya JL, Maixner W, Rao SG (2006) Stress-induced muscle and cutaneous hyperalgesia: differential effect of milnacipran. Physiol Behav 88:82–87
Surh Y-J, Chun K-S, Cha H-H, Han SS, Keum Y-S, Park K-K, Lee SS (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-κB activation. Mutat Res Fundament Mol Mech Mutagene 480:243–268
Taler M et al (2007) Immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) on human T lymphocyte function and gene expression. Eur Neuropsychopharmacol 17:774–780
Tsuruoka M, Arai Y-CP, Nomura H, Matsutani K, Willis WD (2003) Unilateral hindpaw inflammation induces bilateral activation of the locus coeruleus and the nucleus subcoeruleus in the rat. Brain Res Bull 61:117–123
Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR (2012) A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 26:469–479
Varghese AK, Verdú EF, Bercik P, Khan WI, Blennerhassett PA, Szechtman H, Collins SM (2006) Antidepressants attenuate increased susceptibility to colitis in a murine model of depression. Gastroenterology 130:1743–1753
Yaksh TL (1981) The antinociceptive effects of intrathecally administered levonantradol and desacetyllevonantradol in the rat. J Clin Pharmacol 21(S1):334S–340S
Yang N, Zhang W, Shi XM (2008) Glucocorticoid-induced leucine zipper (GILZ) mediates glucocorticoid action and inhibits inflammatory cytokine-induced COX-2 expression. J Cell Biochem 103:1760–1771
Yaron I, Shirazi I, Judovich R, Levartovsky D, Caspi D, Yaron M (1999) Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures. Arthritis Rheum Off J Am Coll Rheumatol 42:2561–2568
These data were adopted from the Pharm D. thesis of Dr. Rojin Rashtiani. The authors would like to thank Research and Technology Vice-Chancellor of Hamadan University of Medical Sciences (Hamadan, Iran) for supporting this study.
This work was supported by a grant from Research and Technology Vice-Chancellor of Hamadan University of Medical Sciences, Hamadan, Iran (code: 9605103034).
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Haddadi, R., Rashtiani, R. Anti-inflammatory and anti-hyperalgesic effects of milnacipran in inflamed rats: involvement of myeloperoxidase activity, cytokines and oxidative/nitrosative stress. Inflammopharmacol 28, 903–913 (2020). https://doi.org/10.1007/s10787-020-00726-2
- Pain and analgesia
- Inflammatory cytokines