An investigation into the underlying mechanisms of risperidone-induced antinociception through the cholinergic pathway

Abstract

Pain is a complex phenomenon involving the perception of physical discomfort caused by tissue damage in the body. Risperidone, a neuroleptic with dopamine (D2) and serotonin (5-HT2) receptor antagonistic potentials, also exhibits antinociceptive properties, however, its use in the treatment of peripheral nociception has received little attention. Hence, this study evaluated the antinociceptive effects of risperidone and its possible mechanism of action. Ninety Swiss mice (23-30 g) were divided into two phases: antinociceptive and mechanistic. Antinociceptive activity was assessed using acetic acid-induced writhing and formalin-induced paw-licking tests. In each model, mice were grouped (n=6) and treated with distilled water (control), risperidone (0.5,1.0, and 1.5 mg/kg), or indomethacin (10mg/kg). Mechanistic studies involved atropine, propranolol, or naloxone coadministered with risperidone (1.5mg/kg). The results of the studies showed that risperidone significantly decreased neurogenic and inflammatory pain in the paw licking test while risperidone 1.5mg/kg significantly decreased writhing in the acetic acid-induced writhing test. In the mechanistic studies, atropine co-administered with risperidone group showed significantly reversed anti-nociception when compared with risperidone 1.5mg/ kg alone in the paw-licking test model. Histological assessment of the mice paw tissues using Hematoxylin & Eosin, and Giemsa staining techniques revealed improved infiltration of inflammatory cells, which was significantly decreased in mice pre-treated with atropine, further supporting the analgesic potential of risperidone in the study. This study highlights risperidone's antinociceptive potential and suggests its mechanism is mediated via cholinergic pathways, offering insights into its therapeutic applications that can be implore in pain management.

Keywords

Antinociceptive / Cholinergic / Pain / Risperidone

CRediT authorship contribution statement

Lawrence Adedayo: Writing - review & editing, Writing - original draft, Visualization, Validation, Supervision, Methodology, Funding acquisition, Formal analysis, Data curation, Conceptualization. Victor Adesoye: Project administration, Funding acquisition. Olubayode Bamidele: Validation, Supervision, Investigation. Idris Azeez: Writing - review & editing, Writing - original draft, Validation, Resources, Formal analysis. Oyetola Oyebanjo: Writing - original draft, Software, Resources, Data curation. Adeshina Adekeye: Writing - review & editing, Visualization, Validation, Resources, Formal analysis, Data curation. Saminu Samaila: Writing - original draft, Visualization, Validation, Resources, Formal analysis. Nimedia Aitokhuehi: Validation, Supervision, Software, Resources, Formal analysis, Data curation, Conceptualization. Olusegun Adebayo: Validation, Supervision, Software, Formal analysis, Data curation, Conceptualization. Gideon Ojo: Writing - review & editing, Validation, Supervision, Investigation, Funding acquisition, Conceptualization.

Ethical approval

The experiment was approved by the Animal Research Ethics Committee of Bowen University College of Health Sciences and assigned the number BUTH/REC-427. Taking samples from dead or alive was strictly with the accordance of the recommendations of Committee concerning animal welfare during the study time.

Significance statement

Risperidone alleviates nociception in mouse models, and its mechanism appears to involve the cholinergic pathway in this study. This research sheds light on the potential mechanism of risperidone, an atypical antipsychotic, in managing visceral pain. Given that such drugs also mediate effects via serotonergic pathways, their activity through central mechanisms warrants further investigation. Awareness of the antinociceptive properties of atypical antipsychotic drugs has grown, as supported by findings from this study. Future research on large animal models and clinical trials involving volunteer patients should be conducted to evaluate the analgesic potential of risperidone.

Declaration of generative AI in scientific writing

Not applicable.

Funding information

The authors declare that no financial support was received for the research, authorship, or publication of this article.

Data availability

All data sets obtained and analyzed during the current study are available on reasonable request from the corresponding author.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

The authors would like to express their gratitude to the laboratory technical staff of the Department of Physiology, College of Health Sciences, Bowen University Iwo, Nigeria.

References

[1] A.C.C. Williams, K.D. Craig, Updating the definition of pain, Pain 157 (11) (2016) 2420-2423, https://doi.org/10.1097/j.pain.0000000000000613.

[2] S.N. Raja, D.B. Carr, M. Cohen, N.B. Finnerup, H. Flor, S. Gibson, F.J. Keefe, J. S. Mogil, M. Ringkamp, K.A. Sluka, X.J. Song, B. Stevens, M.D. Sullivan, P. R. Tutelman, T. Ushida, K. Vader, The revised international association for the study of pain definition of pain: concepts, challenges, and compromises, Pain 161 (9) (2020) 1976-1982, https://doi.org/10.1097/j.pain.0000000000001939.

[3] D.J. Debono, L.J. Hoeksema, R.D. Hobbs, Caring for patients with chronic pain: pearls and pitfalls, J. Am. Osteopath. Assoc. 113 (8) (2013) 620-627, https://doi.org/10.7556/jaoa.2013.023.

[4] F. Zobdeh, I.I. Eremenko, M.A. Akan, V.V. Tarasov, V.N. Chubarev, H.B. Schiöth, J. Mwinyi, Pharmacogenetics and pain treatment with a focus on non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants: a systematic review, Pharmaceutics 14 (6) (2022) 1190, https://doi.org/10.3390/pharmaceutics14061190.

[5] J.L. Wallace, P. Del Soldato, The therapeutic potential of NO-NSAIDs, Fundam. Clin. Pharmacol. 17 (1) (2003) 11-20, https://doi.org/10.1046/j.14728206.2003.00125.x.

[6] Z. Wang, A. Singh, G. Jones, T. Winzenberg, C. Ding, A. Chopra, S. Das, D. Danda, L. Laslett, B. Antony, Efficacy and safety of turmeric extracts for the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomised controlled trials, Curr. Rheumatol. Rep. 23 (2) (2021) 11, https://doi.org/10.1007/s11926-020-00975-8.

[7] E. Bellotti, G. Contarini, F. Geraci, S.A. Torrisi, C. Piazza, F. Drago, Long lasting rescue of schizophrenia relevant cognitive impairments via risperidone loaded microPlates, Drug Deliv Transl Res 12 (2022) 1829-1842, https://doi.org/10.1007/s11926-020-00975-8.

[8] M.M.H. Lari, H.R. Banafshe, E.S. Hosseini, H.H. Kashani, The effect of risperidone on behavioral reactions and gene expression of pro- and anti-inflammatory cytokines in neuropathic pain model induced by chronic constriction injury of the sciatic nerve in rat, Inflammopharmacology 31 (2023) 2641-2652, https://doi.org/10.1007/s10787-023-01293-y.

[9] L.D. Adedayo, D.A. Olawuyi, A.O. Ojo, O. Bamidele, S.A. Onasanwo, A.O. Ayoka, The role of aripiprazole (an anti-psychotic drug) in the resolution of acute peripheral inflammation in Male Wistar rats, J. Pharm. Res. Int. 17 (6) (2017) 1-8, https://doi.org/10.9734/JPRI/2017/32601.

[10] G.P. Reynolds, Receptor mechanisms of antipsychotic drug action in bipolar disorder-focus on asenapine, Ther. Adv. Psychopharmacol. 1 (6) (2011) 197-204, https://doi.org/10.1177/2045125311430112.

[11] S.K. Rigler, T.I. Shireman, G.J. Cook-Wiens, E.F. Ellerbeck, J.C. Whittle, D.R. Mehr, J.D. Mahnken, Fracture risk in nursing home residents initiating antipsychotic medications, J. Am. Geriatr. Soc. 61 (5) (2013) 715-722, https://doi.org/10.1111/jgs.12216.

[12] D. Mishra, G. Ghosh, P.S. Kumar, P.K. Panda, An experimental study of analgesic activity of selective COX-2 inhibitor with conventional NSAIDs, Asian J. Pharmaceut. Clin. Res. (4) (2004) 974-2441, https://doi.org/10.38164/AJPER/12.3.2023.74-80.

[13] M.A. Emery, S. Eitan, Members of the same pharmacological family are not alike: different opioids, different consequences, hope for the opioid crisis? Prog. Neuropsychopharmacol. Biol. Psychiatry 92 (2019) 428-449, https://doi.org/10.1016/j.pnpbp.2019.02.010.

[14] J.E. Leysen, In vitro and in vivo receptor binding and effects on monamine turnoverin rat brain regions of the novel antipsychotics' risperidone and ocaperidone, Mol. Mol Pharmacol. 41 (1992) 494-508.

[15] Y.K. Jean, M.C. Gitlin, J. Reynolds, K.A. Candiotti, Tramadol-associated hallucinations: a systematic review and narrative synthesis of their pathophysiology, diagnosis, and treatment, Can. J. Anaesth. 67 (3) (2020) 360-368, https://doi.org/10.1007/s12630-019-01548-9.English.

[16] G.T. Carter, V. Duong, S. Ho, K.C. Ngo, C.L. Greer, D.L. Weeks, Side effects of commonly prescribed analgesic medications, Phys. Med. Rehabil. Clin (25) (2014) 457-470, https://doi.org/10.1016/j.pmr.2014.01.007.

[17] M. Juncal-Ruiz, L. Riesco-Dávila, V. Ortiz-García de la Foz, O. Martínez-Garcia, M. Ramírez-Bonilla, J.G. Ocejo-Viñals, J.C. Leza, M. López-Hoyos, B. CrespoFacorro, Comparison of the anti-inflammatory effect of aripiprazole and risperidone in 75 drug-naïve first episode psychosis individuals: a 3 months randomized study, Schizophr. Res. 202 (2018) 226-233, https://doi.org/10.1016/j.schres.2018.06.039.

[18] M.M. Al-min, M.M. Nasir Udda, R.H. Mahmud, Effects of antipyschotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures, Clin. Psychopharmacol. Neurosci. (2013) 144-151, https://doi.org/10.9758/cpn.2013.11.3.144.

[19] S. Sierra, K.H. Muchhala, D.K. Jessup, K.M. Contreras, U.H. Shah, D.L. Stevens, J. J Jimenez, et al., Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice, Neuropharmacology 209 (2022) 108988, https://doi.org/10.1016/j.neuropharm.2022.108988.

[20] I. Hirota, Y. Koyama, S. Shimada, Histochemical analysis of the biphasic properties of formalin pain-induced behavior, Biochem Biophys Rep 34 (2023) 101467, https://doi.org/10.1016/j.bbrep.2023.101467.

[21] M.M.H. Lari, H.R. Banafshe, E.S. Hosseini, H.H. Kashani, The effect of risperidone on behavioral reactions and gene expression of pro- and anti-inflammatory cytokines in neuropathic pain model induced by chronic constriction injury of the sciatic nerve in rat, Inflammopharmacology 31 (2023) 2641-2652, https://doi.org/10.1007/s10787-023-01293-y.

[22] S. Sierra, K.H. Muchhala, D.K. Jessup, K.M. Contreras, U.H. Shah, D.L. Stevens, J. J Jimenez, et al., Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice, Neuropharmacology 209 (2022) 108988, https://doi.org/10.1016/j.neuropharm.2022.108988.

[23] E. Siegmund, R. Cadmus, G. Lu, A method for evaluating both non-narcotic and narcotic analgesics, Proc Soc Exp Biol Med 95 (4) (1957) 729-731, https://doi.org/10.3181/00379727-95-23345.

[24] D. Dubuisson, S.G. Dennis, The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats, Pain 4 (2) (1977) 161-174, https://doi.org/10.1016/0304-3959(77)90130-0.

[25] N. Loganayaki, P. Siddhuraju, S. Manian, Antioxidant, anti-inflammatory and antinociceptive effects of Ammannia baccifera L. (Lythracceae), a folklore medicinal plant, J. Ethnopharmacol. 140 (2012) 230-233, https://doi.org/10.1016/j.jep.2012.01.001.

[26] I.A. Azeez, S.A. Hena, P.O. Ogwujo, J.O. Omirinde, O.M. Akinsola, N.J. Plang, I. J. Gosomji, Comparative skin anatomy of the Nigerian local dogs and pigs, Savannah Veterinary Journal 5 (1) (2022) 20-27, https://doi.org/10.36759/svj.2021.158.

[27] J.D. Loeser, R.D. Treede, The Kyoto protocol of IASP basic pain terminology, Pain 137 (3) (2008) 473-477, https://doi.org/10.1016/j.pain.2008.04.025.

[28] L.D. Adedayo, A.O. Ojo, F.O. Awobajo, B.A. Adeboye, J.A. Adebisi, T.J. Bankole, G. O. Ayilara, O. Bamidele, N.G. Aitokhuehi, S.A. Onasanwo, Methanol extract of Cola nitida ameliorates inflammation and nociception in experimental animals, Neurobiol Pain 5 (2019) 100027, https://doi.org/10.1016/j.ynpai.2019.100027.

[29] S. Hunskaar, K. Hole, The formalin test in mice: dissociation between inflammatory and non-inflammatory pain, Pain (30) (1987) 103-114, https://doi.org/10.1016/0304-3959(87)90088-1.

[30] E. Elisabetsky, T.A. Amador, R.R. Albuquerque, D.S. Nunes, C. Carvalho Ado, Willd. ex R. & S.) Muell. Arg. alkaloids, Analgesic activity of Psychotria colorata ( J. Ethnopharmacol. 48 (2) (1995) 77-83, https://doi.org/10.1016/0378-8741(95)01287-n.

[31] M.A.P. Martins, C.F. Mello, M.A. Rubin, J. Ferreira, H.G. Bonacorso, Antinociceptive effect of novel trihalomethyl-substituted pyrazoline methyl esters in formalin and hot-plate tests in mice, Eur. J. Pharmacol. (581) (2008) 86-96, https://doi.org/10.1016/j.ejphar.2007.11.042.

[32] S. Schreiber, C.G. Pick, The opioid interactions of the antipsychotic medications risperidone and amisulpride in mice and their potential use in the treatment of other non-psychotic medical conditions, Cell. Mol. Neurobiol. 41 (5) (2021) 1077-1084, https://doi.org/10.1007/s10571-020-01001-2.

[33] S. Sierra, K.H. Muchhala, D.K. Jessup, K.M. Contreras, U.H. Shah, D.L. Stevens, J. J Jimenez, et al., Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice, Neuropharmacology 209 (2022) 108988, https://doi.org/10.1016/j.neuropharm.2022.108988.

[34] H.F. Miranda, V. Noriega, F. Sierralta, R. Sotomayor-Zárate, J.C. Prieto, Risperidone in analgesia induced by paracetamol and meloxicam in experimental pain, Fundam. Clin. Pharmacol. 36 (3) (2022) 494-500, https://doi.org/10.1111/fcp.12754.

[35] R.C.M. Ferreira, D.L. de Almeida, I.D.G. Duarte, D.C. Aguiar, F.A. Moreira, T.R. L. Romero, The antipsychotic aripiprazole induces peripheral antinociceptive effects through PI3K γ/NO/cGMP/K_ATP pathway activation, Eur. J. Pain 26 (4) (2022) 825-834, https://doi.org/10.1002/ejp.1910.

[36] S.M. Spampinato ( Ed.), Opioid Receptors: Methods and Protocols, second ed., Springer, New York, NY, 2021. ISBN 9781071608838.

[37] M. Kolasa, J. Solich, A. Faron-Górecka, D. Żurawek, P. Pabian, S. Łukasiewicz, M. Kuśmider, K. Szafran-Pilch, M. Szlachta, M. Dziedzicka-Wasylewska, Paroxetine and low-dose risperidone induce serotonin 5-HT_1Aand dopamine D2 receptor heteromerization in the mouse prefrontal cortex, Neuroscience 377 (2018) 184-196, https://doi.org/10.1016/j.neuroscience.2018.03.004.

[38] C.G. Vargas, H.F. Miranda, F. Sierralta, V. Noriega, J.C. Prieto, Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain, Drug Dev. Res. 80 (4) (2019) 471-474, https://doi.org/10.1002/ddr.21519.

[39] A.S. Nagpal, D.J. Lodge, J.S. Potter, A. Frazer, R. Tragus, M.E. Curtis, A.M. Boley, M. Eckmann, Analgesic effects of oxycodone in combination with risperidone or ziprasidone: results from a pilot randomized controlled trial in healthy volunteers, Front. Pain Res 3 (2022) 752256, https://doi.org/10.3389/fpain.2022.752256.

[40] H. Yousefi-Manesh, P. Dejban, F. Mumtaz, A. Abdollahi, M. Chamanara, A. Dehpour, A. Hasanvand, A. Rashidian, Risperidone attenuates acetic acidinduced colitis in rats through inhibition of TLR4/NF-kB signaling pathway, Immunopharmacol. Immunotoxicol. 42 (5) (2020) 464-472, https://doi.org/10.1080/08923973.2020.1808987.

[41] S. Schreiber, C.G. Pick, The opioid interactions of the antipsychotic medications risperidone and amisulpride in mice and their potential use in the treatment of other non-psychotic medical conditions, Cell. Mol. Neurobiol. 41 (5) (2021) 1077-1084, https://doi.org/10.1007/s10571-020-01001-2.

[42] R. Kuner, T. Kuner, Cellular circuits in the brain and their modulation in acute and chronic pain, Physiol. Rev. 101 (1) (2021) 213-258, https://doi.org/10.1152/physrev.00040.2019.

[43] J. Zugaib, L. Menescal-de-Oliveira, Cholinergic/opioid interaction in anterior cingulate cortex reduces the nociceptive response of vocalization in Guinea pigs, Brain Res. 1671 (2017) 131-137, https://doi.org/10.1016/j.brainres.2017.07.013.

[44] P.V. Naser, R. Kuner, Molecular, cellular and circuit basis of cholinergic modulation of pain, Neuroscience 387 (2018) 135-148, https://doi.org/10.1016/j.neuroscience.2017.08.049.