Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory

Neurobiol Learn Mem. 2013 Oct;105:133-50. doi: 10.1016/j.nlm.2013.06.008. Epub 2013 Jun 22.


Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy-mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain-related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla.

Keywords: 4EBP; 5-HT; 5-aza; 5-azacytidine; Aplysia; BDNF; C/EBP; CAMKII; CBS; CCAAT enhancer binding protein; CCI; CFA; COX-2; CPB; CPEB; CRE; CREB; CREB-binding protein; Ca(2+); Central sensitization; DHPG; DNA methyltransferase; DNA methyltransferase inhibitor; DNMT; DNMTi; DRG; EIF4E; EIF4E binding protein; ERK; Epigenetic; FCS; FK 506 binding protein; FKBP5; FMRFa; HAT; HDAC; HDACi; Histone; IL-6; IP3; ITF; LE; LG; LTD; LTF; LTH; LTP; LTS; Left E cluster; MAPK; MeCP2; Methylation; NF-κB; NO; NRM; NRSE; NRSF; PARP; PGE2; PKA; PKC; PKG; PKM; PSNL; PTM; PTSD; Pi-RNAs; Piwi-interacting RNAs; Pre-Met-ARg-Phe-NH(2); S-adenosyl-methionine; S6 kinase; S6K; SAHA; SAM; SGK1; SGWR; SNI; SNL; STF; SULT1A1; Sensitization; TOR; TSA; TrkB; UCH; VC; ZIP; brain derived neurotrophic factor; cAMP; cAMP response element; cAMP response element binding protein; cAMP-dependent protein kinase; cGMP; calcium; calmodulin-dependent protein kinase II; chronic constriction injury; complete Freund’s adjuvant; cyclic adenosine monophosphate; cyclic guanosine monophosphate; cyclooxygenase-2; cystathionine-β-synthase; cytoplasmic polyadenylation element binding protein; dihydroxyphenylglycine; dorsal root ganglion; eEF2; eukaryotic elongation factor 2; eukaryotic translation initiation factor 4E; extracellular receptor kinase; fast conducting system; histone acetyltransferase; histone acetyltransferase E1A binding protein p300; histone deacetylase; histone deacetylase inhibitor; inositol 1,4,5-trisphosphate; interleukin 6; intermediate-term facilitation; lateral giant neuron; long-term depression; long-term facilitation; long-term hyperexcitability; long-term potentiation; long-term sensitization; methyl-CpG-binding protein 2; mitogen activated protein kinase; neuron-restrictive silence factor; neuron-restrictive silencer element; nitric oxide; nuclear factor kappa-light-chain-enhancer of activated B cells; nucleus raphe magnus; p300; partial sciatic nerve ligation; poly-(ADP-ribose) polymerase; post-translational modifications; post-traumatic stress disorder; prostaglandin E2; protein kinase C; protein kinase G; protein kinase M; serotonin; serum- and glucocorticoid-inducible kinase; short-term facilitation; siphon-gill withdrawal reflex; spared nerve injury; spinal nerve ligation; suberoylanilide hydroxamic acid; sulfotransferase family 1A, phenol-preferring, member 1; target of rapamycin; trichostatin A; tyrosine kinase receptor B; ubiquitin C-terminal hydrolase; ventrocaudal clusters; zeta inhibitory peptide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Aplysia
  • Central Nervous System Sensitization / genetics*
  • Conditioning, Psychological / physiology*
  • Epigenesis, Genetic*
  • Humans
  • Memory / physiology*
  • Mice
  • Neuronal Plasticity / genetics*
  • Pain / physiopathology*
  • Rats
  • Signal Transduction