Table 3.

Key References Demonstrating an Important Role of Translation Regulation in Dorsal Horn Plasticity in Pain Models

Refs	Signaling pathway	Pain model/target	Key findings
Zhuo et al. 1998 [95]	General translation regulation	Formalin	First report to show that spinal inhibition of protein synthesis inhibits second phase of formalin test
Price et al. 2007 [37]	mTORC1	Formalin, peripheral nerve injury, mGLuR1/5 activation	Phase II formalin- and mGluR1/5-mediated behaviors are decreased in Fmr1-knockout mice and that spinal inhibition of mTORC1 inhibits pain behaviors in both of these models at late time points
Asante et al. 2009 [52], Asante et al. 2010 [96]	mTORC1	Formalin, peripheral nerve injury, electrophysiology	Used spinal electrophysiology to show that inhibition of mTORC1 with rapamycin causes a decrease in sensitization of deep dorsal horn neurons in response to formalin or peripheral nerve injury
Asiedu et al. 2011 [97], Melemedjian et al. 2013 [98]	BDNF signaling to mTORC1 leading to atypical PKC translation	Hyperalgesic priming	Demonstrated that mTORC1-mediated translation regulates atypical PKC translation in dorsal horn, contributing to initiation of hyperalgesic priming; [98] also showed that this process is regulated by BDNF signaling
Xu et al. 2014 [7]	mTORC1	Opioid tolerance, opioid hyperalgesia	Chronic opioid treatment increases spinal mTORC1 activity; inhibition of this signaling pathway blocks and reverses opioid tolerance and opioid-induced hyperalgesia
Bonin and De Koninck 2014 [74], Kim et al. 2015 [77]	Spinal reconsolidation	Capsaicin-induced pain hypersensitivity	[74] showed that a reconsolidation window can be opened in spinal dorsal horn that allows for reversal of pain hypersensitivity when that reconsolidation event is paired with a protein synthesis inhibitor. [77] showed that this paradigm can be generalized to hyperalgesic priming models where dopamine D1/D5 agonists open a reconsolidation window that is also sensitive to protein synthesis inhibition
Khoutorsky et al. 2015 [53]	4E-BPs	Enhanced mechanical pain with 4E-BP1 deletion	Genetic removal of 4E-BP1 causes mechanical hypersensitivity (but no changes in thermal pain) that is accounted for by increased neuroligin 1 expression and increased excitatory neurotransmission in dorsal horn
Maixner et al. 2015 [99]	AMPK	Peripheral nerve injury	Neuropathic pain leads to downregulation of AMPK activity in dorsal horn. Activating spinal AMPK alleviates neuropathic pain and restores deficits in glial glutamate transporter expression