The Pharmacology of Nociceptor Priming
Nociceptors and neurons in the central nervous system (CNS) that receive nociceptive input show remarkable plasticity in response to injury. This plasticity is thought to underlie the development of chronic pain states. Hence, further understanding of the molecular mechanisms driving and maintaining this plasticity has the potential to lead to novel therapeutic approaches for the treatment of chronic pain states. An important concept in pain plasticity is the presence and persistence of “hyperalgesic priming.” This priming arises from an initial injury and results in a remarkable susceptibility to normally subthreshold noxious inputs causing a prolonged pain state in primed animals. Here we describe our current understanding of how this priming is manifested through changes in signaling in the primary nociceptor as well as through memory like alterations at CNS synapses. Moreover, we discuss how commonly utilized analgesics, such as opioids, enhance priming therefore potentially contributing to the development of persistent pain states. Finally we highlight where these priming models draw parallels to common human chronic pain conditions. Collectively, these advances in our understanding of pain plasticity reveal a variety of targets for therapeutic intervention with the potential to reverse rather than palliate chronic pain states.
KeywordsAtypical PKC AMPA NMDA mTORC1 PKC Epac Hyperalgesic priming Prostaglandins NGF Interleukin 6
This work was supported by NIH grants NS065926 and GM102575 to T.J.P.
- Atkins CM, Davare MA, Oh MC, Derkach V, Soderling TR (2005) Bidirectional regulation of cytoplasmic polyadenylation element-binding protein phosphorylation by Ca2+/calmodulin-dependent protein kinase II and protein phosphatase 1 during hippocampal long-term potentiation. J Neurosci 25:5604–5610CrossRefPubMedGoogle Scholar
- Cabanero D, Celerier E, Garcia-Nogales P, Mata M, Roques BP, Maldonado R, Puig MM (2009b) The pro-nociceptive effects of remifentanil or surgical injury in mice are associated with a decrease in delta-opioid receptor mRNA levels: prevention of the nociceptive response by on-site delivery of enkephalins. Pain 141:88–96CrossRefPubMedGoogle Scholar
- Eijkelkamp N, Wang H, Garza-Carbajal A, Willemen HL, Zwartkruis FJ, Wood JN, Dantzer R, Kelley KW, Heijnen CJ, Kavelaars A (2010) Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK. J Neurosci 30:12806–12815CrossRefPubMedGoogle Scholar
- Ma W, Ribeiro-da-Silva A, De Koninck Y, Radhakrishnan V, Cuello AC, Henry JL (1997) Substance P and enkephalin immunoreactivities in axonal boutons presynaptic to physiologically identified dorsal horn neurons. An ultrastructural multiple-labelling study in the cat. Neuroscience 77:793–811CrossRefPubMedGoogle Scholar
- Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ (1999) Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A 96:9385–9390CrossRefPubMedCentralPubMedGoogle Scholar
- Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A, Khoutorsky A, Johnson J, Peebles KA, Lepow T, Sonenberg N, Dussor G, Price TJ (2011) Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain 7:70CrossRefPubMedCentralPubMedGoogle Scholar
- Rivat C, Bollag L, Richebe P (2013) Mechanisms of regional anaesthesia protection against hyperalgesia and pain chronicization. Curr Opin Anaesthesiol 26(5):621–625Google Scholar
- Wang X, Flynn A, Waskiewicz AJ, Webb BL, Vries RG, Baines IA, Cooper JA, Proud CG (1998) The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J Biol Chem 273:9373–9377CrossRefPubMedGoogle Scholar
- Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G, Morenilla-Palao C, Stirling C, Fitzgerald M, McMahon SB, Rios M, Wood JN (2006) Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci 31:539–548CrossRefPubMedGoogle Scholar