Invertebrate Neuroscience

, 17:10 | Cite as

The selective serotonin reuptake inhibitor fluoxetine increases spontaneous afferent firing, but not mechanonociceptive sensitization, in octopus

  • Paul V. Perez
  • Hanna M. Butler-Struben
  • Robyn J. CrookEmail author
Short Communication


Serotonin is a widely studied modulator of neural plasticity. Here we investigate the effect of fluoxetine, a selective serotonin reuptake inhibitor, on short-term, peripheral nociceptive plasticity in the neurologically complex invertebrate, octopus. After crush injury to isolated mantle (body wall) tissue, application of 10 nM fluoxetine increased spontaneous firing in crushed preparations, but had a minimal effect on mechanosensory sensitization. Effects largely did not persist after washout. We suggest that transiently elevated, endogenous serotonin may help promote initiation of longer-term plasticity of nociceptive afferents and drive immediate and spontaneous behaviors aimed at protecting wounds and escaping dangerous situations.


SSRI Fluoxetine Octopus Nociceptive sensitization Injury 



Central nervous system




Artificial seawater


Fluoxetine (in solution, 10 nM in ASW)


Peripheral nervous system


Long-term memory


Short-term memory


Spontaneous activity


Selective serotonin reuptake inhibitor



We thank members of the Crook Lab for assisting with animal care, and Peyman Bastani and Robert Dasmarinus for conducting additional data analysis. Funding was provided from a DRC Grant from SF State, and from start-up funds to RJC, and an NIH MBRS-RISE (R25-GM059298) to PVP.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Albertin CB, Simakov O, Mitros T et al (2015) The octopus genome and the evolution of cephalopod neural and morphological novelties. Nature 524:220–224. doi: 10.1038/nature14668 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alupay JS, Hadjisolomou SP, Crook RJ (2014) Arm injury produces long-term behavioral and neural hypersensitivity in octopus. Neurosci Lett 558:137–142CrossRefPubMedGoogle Scholar
  3. Anjaneyulu M, Chopra K (2006) Possible involvement of cholinergic and opioid receptor mechanisms in fluoxetine mediated antinociception response in streptozotocin-induced diabetic mice. Eur J Pharmacol 538:80–84. doi: 10.1016/j.ejphar.2006.03.067 CrossRefPubMedGoogle Scholar
  4. Barbas D, DesGroseillers L, Castellucci VF et al (2003) Multiple serotonergic mechanisms contributing to sensitization in Aplysia: evidence of diverse serotonin receptor subtypes. Learn Mem 10:373–386. doi: 10.1101/lm.66103 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152CrossRefPubMedGoogle Scholar
  6. Bellier J-P, Xie Y, Farouk SM et al (2017) Immunohistochemical and biochemical evidence for the presence of serotonin-containing neurons and nerve fibers in the octopus arm. Brain Struct Funct. doi: 10.1007/s00429-017-1385-3 PubMedGoogle Scholar
  7. Calvino MA, Iscla IR, Szczupak L (2005) Selective serotonin reuptake inhibitors induce spontaneous interneuronal activity in the leech nervous system. J Neurophysiol 93:2644–2655. doi: 10.1152/jn.01181.2004 CrossRefPubMedGoogle Scholar
  8. Crook RJ, Lewis T, Hanlon RT, Walters ET (2011) Peripheral injury induces long-term sensitization of defensive responses to visual and tactile stimuli in the squid Loligo pealeii, Lesueur 1821. J Exp Biol 214:3173–3185. doi: 10.1242/jeb.058131 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Crook RJ, Dickson K, Hanlon RT, Walters ET (2014) Nociceptive sensitization reduces predation risk. Curr Biol 24:1121–1125. doi: 10.1016/j.cub.2014.03.043 CrossRefPubMedGoogle Scholar
  10. di Pauli von Treuheim T, Oshima M, Crook RJ et al (2014) Serotonin evokes nociceptor hyperexcitability in Doryteuthis (Loligo) pealeii peripheral nervous system. In: Abstracts of the 2014 Marine Biological Laboratory Undergraduate Research SymposiumGoogle Scholar
  11. Ernberg M, Hedenberg-Magnusson B, Kurita H, Kopp S (2006) Effects of local serotonin administration on pain and microcirculation in the human masseter muscle. J Orofac Pain 20:241–248PubMedGoogle Scholar
  12. Hanlon RT, Messenger JB (1996) Cephalopod behaviour. Cambridge University Press, CambridgeGoogle Scholar
  13. Iwasaki T, Otsuguro K, Kobayashi T et al (2013) Endogenously released 5-HT inhibits A and C fiber-evoked synaptic transmission in the rat spinal cord by the facilitation of GABA/glycine and 5-HT release via 5-HT(2A) and 5-HT(3) receptors. Eur J Pharmacol 702:149–157. doi: 10.1016/j.ejphar.2013.01.058 CrossRefPubMedGoogle Scholar
  14. Marinesco S, Carew TJ (2002) Serotonin release evoked by tail nerve stimulation in the CNS of Aplysia: characterization and relationship to heterosynaptic plasticity. J Neurosci 22:2299–2312PubMedGoogle Scholar
  15. Matsumoto K, Puia G, Dong E, Pinna G (2007) GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress 10:3–12. doi: 10.1080/10253890701200997 CrossRefPubMedGoogle Scholar
  16. Muñoz-Islas E, Vidal-Cantú GC, Bravo-Hernández M et al (2014) Spinal 5-HT5A receptors mediate 5-HT-induced antinociception in several pain models in rats. Pharmacol Biochem Behav 120:25–32. doi: 10.1016/j.pbb.2014.02.001 CrossRefPubMedGoogle Scholar
  17. Oshima M, di Pauli von Treuheim T, Carroll J et al (2016) Peripheral injury alters schooling behavior in squid, Doryteuthis pealeii. Behav Processes 128:89–95. doi: 10.1016/j.beproc.2016.04.008 CrossRefPubMedGoogle Scholar
  18. Rahn EJ, Guzman-Karlsson MC, Sweatt D (2013) Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. Neurobiol Learn Mem 105:133–150CrossRefPubMedPubMedCentralGoogle Scholar
  19. Shomrat T, Feinstein N, Klein M, Hochner B (2010) Serotonin is a facilitatory neuromodulator of synaptic transmission and “reinforces” long-term potentiation induction in the vertical lobe of Octopus vulgaris. Neuroscience 169(1):52-64. doi: 10.1016/j.neuroscience.2010.04.050 CrossRefPubMedGoogle Scholar
  20. Urtikova N, Berson N, Van Steenwinckel J et al (2012) Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain. Pain 153:1320–1331. doi: 10.1016/j.pain.2012.03.024 CrossRefPubMedGoogle Scholar
  21. Wollesen T, Degnan BM, Wanninger A (2010) Expression of serotonin (5-HT) during CNS development of the cephalopod mollusk, Idiosepius notoides. Cell Tissue Res 342:161–178. doi: 10.1007/s00441-010-1051-z CrossRefPubMedGoogle Scholar
  22. Xu F, Luk C, Richard MP et al (2010) Antidepressant fluoxetine suppresses neuronal growth from both vertebrate and invertebrate neurons and perturbs synapse formation between Lymnaea neurons. Eur J Neurosci 31:994–1005. doi: 10.1111/j.1460-9568.2010.07129.x CrossRefPubMedGoogle Scholar
  23. Yang J, Bae HB, Ki HG et al (2014) Different role of spinal 5-HT(hydroxytryptamine)7 receptors and descending serotonergic modulation in inflammatory pain induced in formalin and carrageenan rat models. Br J Anaesth 113:138–147. doi: 10.1093/bja/aet336 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of BiologySan Francisco State UniversitySan FranciscoUSA

Personalised recommendations