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Review
. 2015:227:15-37.
doi: 10.1007/978-3-662-46450-2_2.

The pharmacology of nociceptor priming

Ram Kandasamy  1 , Theodore J Price
Affiliations
Review

The pharmacology of nociceptor priming

Ram Kandasamy et al. Handb Exp Pharmacol. 2015.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Hyperalgesic priming induces a switch in nociceptor second messenger signaling pathways. In a naïve animal, administration (hindpaw injection) of an inflammatory stimulus (e.g., PGE2) results in transient Gs/PKA-mediated acute pain (green curve in (a) and left side in (b)). In the primed animal, the same inflammatory stimulus recruits an additional Gi/o/PKCε and/or an Epac/PKCε-mediated pathway, which contributes to prolonged hyperalgesia (red curve in (a) and right side in (b)) in previously primed animals. Adapted from Reichling and Levine (2009)
Fig. 2
Fig. 2
Translational control pathways involved in hyperalgesic priming. (a) mTORC1 phosphorylates 4EBPs, negative regulators of eIF4F formation. This results in its dissociation from eIF4E, allowing the binding of eIF4E to eIF4G. Phosphorylation of eIF4E (via ERK/MNK1/2) or eIF4G (via mTORC1) enhances the formation of the eIF4F complex, promoting translation. Phosphorylation of CPEB by CamKIIα enhances translation efficiency by increasing the length of the poly A tail in mRNAs containing a CPE sequence. Taken together, eIF4F cap complex formation enhances cap-dependent translation, which is necessary for the induction of priming via translational control of gene expression in sensory afferents. (b) Pharmacological activation of AMPK results in the inhibition of IRS-1, dampening Trk-mediated signaling. AMPK activation also results in TSC2 phosphorylation, thereby inhibiting mTORC1. Moreover, AMPK phosphorylates BRaf leading to inhibition of ERK signaling. Taken together, AMPK activation decreases activity-dependent translation by turning off both the ERK and mTORC1 pathways, presenting a novel opportunity to prevent or reverse hyperalgesic priming. Adapted from Melemedjian et al. (2010) and Price and Dussor (2013)
Fig. 3
Fig. 3
The role of aPKCs in hyperalgesic priming initiation and maintenance. (a) Nociceptor activation leads to spinal BDNF release and a postsynaptic mTORC1-dependent translation of aPKC protein following trkB activation. These newly synthesized aPKCs are then phosphorylated by PDK1. Increased levels and phosphorylation of aPKCs are thought to be involved in initiating priming. (b) Once priming is established, increased aPKC protein and phosphorylation leads to a constitutive increase in AMPAR trafficking to the postsynaptic membrane. This appears to be regulated by BDNF signaling via trkB with BDNF potentially being released from postsynaptic dendrites in the maintenance stage of priming. Presynaptic trkB may also be activated by increased BDNF action in primed animals. Once established, hyperalgesic priming can be permanently reversed by inhibition of aPKCs with ZIP, by disruption of AMPAR trafficking with pep2M, or via inhibition of trkB/BDNF signaling with ANA-12 or trkB-Fc, respectively. Adapted from Price and Ghosh (2013)
Fig. 4
Fig. 4
Signaling pathways regulating endogenous opioid control of hyperalgesic priming. Prior to injury, MORs do not have constitutive activity and nociceptive input to the CNS is absent. However, after injury, nociceptor firing induces activity in CNS circuits leading to release of endogenous opioid peptides in the dorsal horn and the eventual development of MOR constitutive activity resulting in agonist-independent modulation of pain responses. Upon infusion of the MOR inverse agonist naltrexone, AC1 is disinhibited, likely in an NMDA receptor-dependent fashion, allowing for superactivation of cAMP and the reinstatement of hyperalgesia. Adapted from Corder et al. (2013)
Fig. 5
Fig. 5
Opioids given as postsurgical analgesics can exacerbate priming in animal models. Upon incision of the hindpaw, withdrawal thresholds in animals not receiving analgesics drop significantly compared to animals treated with opioids at the time of incision. Following resolution of the initial hyperalgesia, when carrageenan is subsequently injected into the contralateral hindpaw, withdrawal thresholds drop in both groups; however, animals previously treated with opioids demonstrate an exaggerated hyperalgesia to the same stimulus, suggesting that opioids, despite their analgesic effect, exacerbate nociceptive priming induced by injury
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