Review
Synaptic plasticity in pathological pain

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Highlights

  • Synapses in nociceptive pathways adapt strength in an activity-dependent manner.

  • Synaptic plasticity in nociceptive pathways is both functional and structural.

  • We review the molecular mechanisms of synaptic plasticity in nociceptive pathways.

  • Both pre- and post-synaptic mechanisms are involved in spinal synaptic plasticity.

Chronic pain represents a major challenge to clinical practice and basic science. Excitatory neurotransmission in somatosensory nociceptive pathways is predominantly mediated by glutamatergic synapses. A key feature of these synapses is their ability to adapt synaptic strength in an activity-dependent manner. Such disease-induced synaptic plasticity is paramount to alterations in synaptic function and structure. Recent work has recognized that synaptic plasticity at both excitatory and inhibitory synapses can function as a prime mechanism underlying pathological pain. In this review, cellular and molecular mechanisms underlying synaptic plasticity in nociceptive pathways will be reviewed and discussed. New insights derived from these advances are expected to expedite development of novel interventional approaches for treatment of pathological pain.

Section snippets

Key synapses in the nociceptive pathways

The somatosensory nociceptive system is composed of peripheral sensory neurons, intricate circuits at the level of the spinal dorsal horn and brainstem, and a large number of brain regions, which together generate the complex, multidimensional experience of pain. Excitatory transmission at key synapses along this entire pathway constitutes a basic substrate for the discriminative and affective components of pain. A key property of this system is its plasticity: that is, its ability to change in

Plasticity of synaptic transmission at nociceptive synapses

Having taken a look at the key synaptic players (Box 1), we now come to the fascinating field of activity-dependent plasticity of synaptic transmission. It is now a widely appreciated principle in neuroscience that synaptic strength can vary significantly in a context-dependent manner, ranging from the extremes of potentiated synapses to synapses that are silent under physiological conditions (silent synapses) (see Glossary) [5]. Thus, the strength of synaptic transmission at nociceptive

Short-term synaptic plasticity

Short-term synaptic plasticity, referred to as changes in synaptic efficacy that occur over milliseconds to minutes, has been the subject of intense study for decades and is believed to serve as an important element of information processing, including processing of nociceptive inputs in neuronal networks [6]. In the nociceptive system, all levels of pain processing in the central nervous system (CNS) are associated with short-term plasticity (Figure 1). For instance, in the spinal cord, trains

Mechanisms of functional plasticity in nociceptive pathways

In principle, LTP can be induced and/or expressed by presynaptic mechanisms (an increase in transmitter release) or by postsynaptic mechanisms (an increase in postsynaptic responsiveness), or by a combination thereof. In the hippocampus, the pre- versus postsynaptic locus in the expression of LTP has been a matter of much debate 70, 71.

Prevention and reversal of synaptic plasticity in pathological pain

LTP induction can be prevented by blockade of the above-mentioned essential elements of signal transduction pathways, leading to spinal and cortical LTP. For instance, spinal LTP is prevented by low dose of μ-opioid receptor agonist fentanyl or DAMGO 10, 96, clonidine [97], benzodiazepine diazepam [98], NMDAR antagonist 26, 31, 32, or NK1 or NK2 receptor antagonists 31, 32, 99. Drugs such as AC1 inhibitor NB001 and NMDA GluN2B receptor antagonists are effective in preventing cortical LTP [25].

Concluding remarks and future directions

In conclusion, a comprehensive set of genetic, pharmacological, physiological, and novel imaging approaches has generated novel insights on synaptic mechanisms of the shift between physiological pain and chronic, pathological pain. Most recent studies have demonstrated that at spinal nociceptive synapses, in addition to postsynaptic mechanisms involved in induction of long-term plasticity, a presynaptic mechanism involving increased neurotransmitter release from nociceptor terminals is required

Disclaimer statement

The authors declare no completing financial interests.

Acknowledgments

This work was supported by grants from the Natural Science Foundation of China (No. 31171065), the National Basic Research Program (973 Program, No. 2014CB543200), and the Program for Shaanxi Province Key Research Team of Science and Technology Innovation (No. 2012 KCT-14) to C.L., grants from Deutsches Forschungsgemeinschaft (DFG) to R.K., and an ERC Advanced Investigator Grant to R.K., as well as by grants from the DFG and the EU-consortium, Brain Train, to T.K. R.K. and T.K. are members of

Glossary

Early- and late-phase LTP
LTP occurs in two phases. Early-phase LTP is independent on de novo protein synthesis and lasts for up to 2–3 hours. Late-phase LTP involves protein synthesis and lasts longer than 3 hours, up to the life span of an animal and may be accompanied by structural changes at synapses.
Long-term depression (LTD)
a long-lasting decrease of the response of a postsynaptic nerve cell to stimulation across the synapse that occurs with repeated stimulation, which lasts for an

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