Trends in Neurosciences
Central sensitization and LTP: do pain and memory share similar mechanisms?
Section snippets
Why pain, memory and synaptic plasticity?
Living organisms need to be able to sense their immediate environment if they are to withdraw from or avoid potentially hazardous situations. Development in multicellular creatures of the nervous system – a specialized apparatus to effect detection and reaction to external stimuli – together with evolution of specific transduction proteins, has enabled accurate differentiation between innocuous and noxious stimuli. This early warning system was further elaborated by development of the capacity
Pain: peripheral versus central sensitization
In mammals, the early-warning protective pain that occurs in response to noxious stimuli (nociceptive pain) is mediated by specialized high-threshold primary sensory neurons, the nociceptors. Activation of transduction molecules, such as the transient receptor potential ion channel TRPV1, after a heat stimulus (>42 °C) generates inward currents in the nociceptor peripheral terminal. If these currents exceed a threshold value, they cause action potentials in the nociceptor axon; following
Windup – reversible synaptic plasticity during a noxious stimulus
Windup is a form of homosynaptic activity-dependent plasticity characterized by a progressive increase in action potential output from dorsal horn neurons during a train of repeated low-frequency C-fiber or nociceptor stimuli [34]. Unmyelinated C-fiber nociceptor afferents coexpress glutamate and neuropeptide neurotransmitters [substance P and calcitonin-gene-related peptide (CGRP)] [35]. As a consequence, activation of these fibers elicits slow synaptic potentials lasting several-hundred
Mechanisms of late-onset transcription-dependent central sensitization
It is just beginning to be appreciated that nociceptor activity and/or peripheral tissue inflammation produces long-term changes in synaptic efficacy in the dorsal horn. Whether there is late-phase LTP in the spinal cord is not yet known. However, like consolidation of memory in the cortex, late-onset plasticity in the dorsal horn involves activation of transcription factors and alterations in transcription. Such changes take several hours to manifest, last for prolonged periods, and can be
Resemblance between the early phase of CA1 hippocampal LTP and activity-dependent classical central sensitization
The postsynaptic mechanisms responsible for the induction and expression of the early phase of CA1 hippocampal LTP 88, 89 are compared here with known or proposed mechanisms of classical central sensitization. In general, however, considerably less is known about the precise cellular mechanisms of central sensitization than about hippocampal LTP.
Hippocampal LTP displays several basic properties relevant to its role in memory consolidation. LTP is input-specific, meaning that synaptic strength
Central sensitization and clinical pain
Central sensitization plays a major role in the generation of acute post-operative and post-traumatic pain 102, 103, migraine and neuropathic pain 104, 105, 106, 107, 108. Some clinical conditions, such as tension-type headache and fibromyalgia, appear not to be a reaction to a peripheral pathology but instead an expression of the presence of central sensitization 104, 109. Why central sensitization manifests – apparently spontaneously – in these patients remains to be established.
Multiple molecules mediating LTP and central sensitization
More than 100 molecules have been implicated as mediators or modulators of hippocampal LTP [110]. Many of these are also involved in spinal central sensitization and the subsequent generation of pain hypersensitivity (Table 1). The similarities between these two forms of synaptic plasticity are striking, particularly post-translational regulation of AMPA and NMDA receptors, trafficking of AMPA receptors, and activation of the ERK–CREB pathway. However, there are also differences. For example, NK
Concluding remarks
The prolonged sensitization of pain transmission neurons after peripheral injury, by producing pain hypersensitivity and thereby promoting repair, is an adaptive response. This is usually followed by return to a normal high-threshold for activation of pain when healing is complete, unless the nervous system is damaged. Targeting the mechanisms responsible for the induction and maintenance of central sensitization is a major component of analgesic therapy that is made difficult by the need to
References (110)
Injury-related behavior and neuronal plasticity: an evolutionary perspective on sensitization, hyperalgesia, and analgesia
Int. Rev. Neurobiol.
(1994)p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia
Neuron
(2002)Sensitization of cat dorsal horn neurons to innocuous mechanical stimulation after intradermal injection of capsaicin
Brain Res.
(1989)Painful neuropathy: altered central processing maintained dynamically by peripheral input
Pain
(1992)Facilitation of the responses of primate spinothalamic cells to cold and mechanical stimuli by noxious heating of the skin
Pain
(1982)Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: the contribution of dorsal horn mechanisms
Pain
(1989)Long-term potentiation in spinothalamic neurons
Brain Res. Brain Res. Rev.
(2002)Chronic pain and medullary descending facilitation
Trends Neurosci.
(2002)Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brain-stem neurones
Pain
(1992)Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin
Pain
(1989)