Cortical plasticity as a new endpoint measurement for chronic pain
© Zhuo; licensee BioMed Central Ltd. 2011
Received: 9 June 2011
Accepted: 28 July 2011
Published: 28 July 2011
Animal models of chronic pain are widely used to investigate basic mechanisms of chronic pain and to evaluate potential novel drugs for treating chronic pain. Among the different criteria used to measure chronic pain, behavioral responses are commonly used as the end point measurements. However, not all chronic pain conditions can be easily measured by behavioral responses such as the headache, phantom pain and pain related to spinal cord injury. Here I propose that cortical indexes, that indicate neuronal plastic changes in pain-related cortical areas, can be used as endpoint measurements for chronic pain. Such cortical indexes are not only useful for those chronic pain conditions where a suitable animal model is lacking, but also serve as additional screening methods for potential drugs to treat chronic pain in humans. These cortical indexes are activity-dependent immediate early genes, electrophysiological identified plastic changes and biochemical assays of signaling proteins. It can be used to evaluate novel analgesic compounds that may act at peripheral or spinal sites. I hope that these new cortical endpoint measurements will facilitate our search for new, and more effective, pain medicines, and help to reduce false lead drug targets.
Pain has at least two different major forms: acute pain that is short-lasting, and often serves as protective and learning signals. It is also called physiological pain in part due to its important physiological functions. The second form is chronic pain that is long-lasting pain caused by injury to tissue or nerve systems. Although it also informs animal or patients the location of the injured area, the long-term component of chronic pain is not physiological critical, and it causes cognitive impairment, emotional sufferings, loss of sleep and mood disorders. Thus, it is also called pathological pain.
The progress made in human brain imaging has significantly improved our understanding of chronic pain. Brain imaging in conscious humans allow us to evaluate roles of various cortical areas in pain, and brain activation by painful stimuli can be evaluated and compared with patient's psychological reports of pain and emotional feelings . Recently such techniques have also been successfully used to measure psychological pain or empathy of pain [2, 3]. And the measurement of reflexive responses in such human studies is not needed. Can we achieve similar aims in animal studies of chronic pain? In this review, I would like to propose that neurobiological indexes obtained from pain-related cortical neurons can be used as new cortical endpoints of pain measurements in animal models of chronic pain. The use of such new endpoints will allow us to study certain types of chronic pain that is difficult to be investigated in animal models due to the lack of motor responses. They are: headaches, seizure induced pain, phantom pain, spinal injury induced pain and chronic back pain. Furthermore, these new endpoints provide mechanism based measurements of chronic pain in animal models, and could be used as better assays for screening potential new drugs for treating chronic pain. It is important to point out that I am not proposing to use those new endpoints to replace the existing behavioral models of chronic pain such as measuring threshold in hyperalgesia and behavioral responses to allodynic stimulation in chronic pain conditions. The combination of these cortical and behavioral endpoints can provide excellent pain endpoint measurements with solid basic neurobiological mechanisms. The new cortical endpoints can be also used effectively for basic investigation of pain mechanisms at peripheral tissue/nerve, spinal cord, and subcortical areas.
Problems that we are facing: drug discovery and translational medical researches
While animal models of chronic pain have greatly facilitated our understanding of basic pain mechanisms, there are still many major problems that cannot be solved using animal behavioral models. Many forms of clinical pain cannot be mimicked in animal models. For example, it is very difficult to measure 'phantom' pain in amputated animals; and it is impossible to measure nociceptive withdrawal responses in animals with spinal cord injuries. Mimicking headaches and chronic back pain in animals is also proved to be extremely difficult, since there is not a clear behavioral motor response related to such pain that can be measured. Furthermore, even in many pain conditions that the measurement in animal behavioral responses to pain are possible, the pain index is often affected by unwanted side effects on motor or pre-motor functions. For example, in case of animal models of chemotherapy induced neuropathic pain, the same chemicals also caused injury to motor neurons/nerves. Defects in motor functions directly affect the measurement of nociceptive responses, if only motor responses are used as pain index such as withdrawal thresholds or latencies. Finally, most of potential analgesic drugs also act on motor neurons non-selectively. There is great need to develop additional non-behavioral measurements for chronic pain.
Human imaging provides direct evidence for the roles of cortex in chronic pain
Cortical areas that are implicated in chronic pain conditions by human brain imaging fMRI that are difficult to be investigated by traditional animal pain models
Clinical pain conditions
SCI induced pain
Chronic back pain
Altered excitatory transmission
Related to increased imaged activity
Increased activity with imaged pain
Chronic back pain
Hypothically induced pain
Altered excitatory transmission
Increased imaged activity
Increased imaged activity
SCI induced pain
Chronic back pain
Hypothically induced pain
Altered brain metabolism
Related to increased imaged activity
Increased activity with imaged pain
Correlated with spontaneous pain; reduced gray matter density
Increased imaged activity
SCI induced pain
Altered sensory transmission
Correlation of cortical reorganization
Correlated with cortical reorganization
Classical pain endpoints ---behavioral models of chronic pain
In basic research area, behavioral studies have been commonly used for measuring endpoint of chronic pain. Most of pharmaceutical drug discovery is focused on two major areas: target proteins and the behavioral endpoints, at least to my knowledge. The behavioral evaluations in animal models of chronic pain are used as the end point for preclinical studies. Despite many limitations of behavioral tests (any pre-motor or motor side effects of drugs or gene mutant can easily affect behavioral responses in freely moving conditions), these 'analgesic' indexes are commonly used, because it is economic, fast, and easily understood by laypersons such as private investors.
The failure to provide consistent non-behavioral endpoints for chronic pain also complicates drug discovery; and too many potential lead drugs work well in animal models of chronic pain. In any pain-related conferences held in recent years, you often hear much more positive drug target proteins than negative ones. Furthermore, the failure to require solid basic scientific evidence by the drug regulator encourages the cheap- and short-cut experimental approaches used by private investors and drug developers. Furthermore, many of these 'analgesic drugs' failed to be translated into clinical drugs, in part due to the fact that only behavioral endpoints were used in many of these preclinical studies.
Clinical image studies of those unstudied chronic pain
It is easy to tell humans are different from animals in term of reporting pain, although humans complain about pain for just for pain. Previous studies reported that animal vocalization activities may be used to measure pain or especially spontaneous pain [11–13]. However, these indexes prove to be difficult to be used, since animals also generate vocalization activities under other normal physiological conditions such as sex mating . Recent human studies using brain imaging have provided key evidence for the involvement of central nervous systems in several chronic pain conditions that cannot be mimicked in animal models. These include headache, phantom pain, back pain, pain related to spinal cord injury, and patient with functional bowel disorder [14, 15]. For example, Willoch et al (2000) reported that in human amputees the activity increased in the ACC and posterior cingulate as well as thalamus is correlated with pain reported in phantom limb, while the activity in the supplementary motor cortex and primary sensorimotor cortex is related to the phantom limb movement . Apkarian et al (2004) reported that chronic back pain is associated with decreased prefrontal and thalamic gray matter density , and altered neural activity in the PFC .
Recent studies of neural correlates of social exclusion by neuroimaging study found that the ACC is more active during exclusion rather than during inclusion , suggesting that psychological rejection in social exclusion also triggers pain-related cortical areas. In case of patients with spinal cord injury, it has been reported that the magnitude of activation in the perigenual ACC and right dorsolateral PFC was significantly correlated with absolute increases in pain intensity triggered by movement imagery . Similar findings have also been reported in patients with chronic low back pain . These human studies are in consistent with previous anatomic studies in animals that somatosensory cortex reorganized itself after spinal cord injury . Cumulative human studies data consistently indicate that cortical activity plays an important role in chronic pain. In many cases, changes in cortical activities without any peripheral stimuli (including spontaneous pain conditions) are sufficient to produce pain in patients.
A proposal for using cortical plasticity as the endpoint measurements for chronic pain
Proposed cortical markers for measuring pain endpoints in chronic pain
Immediate early gene
Activation of c-Fos; Egr1; pCREB
Enhanced AMPA receptor mediated EPSCs
Paired-pulse facilitation (PPF)
NMDA NR2B receptor
Enhanced NR2B sensitive EPSCs
More sensitive to ZIP inhibition
AMPA receptor GluR1
Increased membrane bind AMPA receptor
Increased phosphorylation at PKA site
In vivo field LTP
Injury induced LTP
Outgrow of neuronal dendrites and increased spine density
Brain imaging & in vivo whole-cell
Increased spike responses to non-noxious stimuli
Enhanced cortical activities before and/or after peripheral stimuli
1. Activity-dependent immediate early gene (IEG)
Activity-dependent immediate early genes are known to be activated by neuronal activity in the central nervous system. Peripheral noxious stimuli or injury triggered activation of c-Fos and phosphorylation of cAMP response element binding protein (pCREB) in the spinal cord dorsal horn neurons [21, 8]. Such activation in the spinal cord dorsal horn neurons can be inhibited or blocked by drugs or inhibited behavioral sensitization. It is believed that these activity-activated immediate early genes may contribute to long-term plastic changes in spinal sensory synapses, and thus contribute to behavioral sensitization. It is expected that analgesics that acts at the level of spinal cord or periphery for the treatment of chronic pain should at least partially reduce activation of IEGs triggered by the injury.
Using gene knockout mice, it has been shown that the amount of IEG activation may be related to behavioral pain phenotypes. In adenylyl cyclase subtype 1 (AC1) or AC1 and AC8 knockout mice, it has been shown that chronic inflammatory pain and neuropathic pain were significantly reduced. Consistently, pCREB immunoreactivity induced by hindpaw inflammation was also reduced in AC1, AC8, or AC1&8 double knockout (DKO) mice. Activation of IEGs is also noted in other cortical areas such as IC . Similar to the ACC, the amount of gene expression is likely also related to behavioral pain phenotypes. Interestingly, fear condition, a form of emotional learning, also triggered IEGs in cortical neurons . Activation of Ca2+-calmodulin-dependent protein kinase IV (CaMKIV) is functionally important for activation of IEGs as well as behavioral memory ; indicating that different intracellular signaling pathways may be involved in mediating fear and chronic pain.
2. Cortical potentiation
Similar changes are found in ACC neurons in animal models of inflammation induced by complete Freund's adjuvant (CFA) . CFA injection caused significant potentiation of the input-output relationship of the glutamate mediated excitatory transmission in the ACC of adult mice. Similar changes were found in animals with inflammation in rats (CFA model). Bie et al (2010) reported that CFA inflammation in rats triggered increased AMPA receptor mediated responses in ACC neurons with observed leftward shift of the input-out curves .
3. Presynaptic enhancement of glutamate release
Paired-pulse facilitation (PPF) is a transient form of plasticity commonly used as a measure of presynaptic function, in which the response to the second stimulus is enhanced as a result of residual calcium in the presynaptic terminal after the first stimulus [34, 36]. In control mice, PPF was observed at different stimulus intervals of 35, 50, 75, 100, and 150 ms. After nerve ligation, there was a significant reduction in PPF in ACC neurons compared with those from control mice. The changes in PPF ratio is selective for neurons in layer II/III, no obvious changes were detected in deeper neurons in the ACC. These results indicate that presynaptic enhancement of the excitatory synaptic transmission selectively occurs in the layer II/III of the ACC after nerve injury (Figure 4). Similar changes in PPF ratio are found in ACC neurons of animals with CFA inflammation , indicating that presynaptic enhancement of glutamate release is also shared by peripheral inflammation.
In addition to the use of PPF in the ACC after peripheral nerve injury, AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in ACC neurons in the presence of 0.5 μM tetrodotoxin (TTX) were also found to be affected. After peripheral nerve injury, there was an obvious increase of mEPSC frequency in ACC neurons compared with that of control group. Furthermore, there was significant difference in the amplitude of mEPSCs between the two groups, indicating postsynaptic changes in AMPA receptor mediated responses (see below). By contrast, no significant change in mEPSCs amplitudes is detected in animal model of inflammation . However, this does not completely rule out possible postsynaptic changes that may contribute to inflammatory pain in the ACC.
In a recent study, the use of c-Fos transgenic mice allows one to selectively record pain-trigger cortical cells . The combination of c-Fos transgenic mice and PPF can help to detect selective changes in pain-activated synapses.
4. Postsynaptic glutamate mediated responses
AMPA receptors without GluR2 are Ca2+ permeable and inwardly rectifying [38–40]. Inward rectification occurs by voltage-dependent blockade by polyamines . To identify whether there are inwardly rectifying properties of AMPA receptors as a result of an alteration of their subunit composition in ACC neurons after nerve injury, AMPA receptor-mediated EPSCs were induced at the holding potentials of -65, -5, and +35 mV in ACC neurons. We found that there was significant difference in the rectification of AMPA receptor-mediated transmission in the ACC between control and nerve-ligated mice . Consistently, when the mean current-voltage (I-V) relationship was plotted, less inward currents were found in ACC neurons from mice with nerve injury compared with control mice . These results demonstrate that AMPA receptor in ACC neurons has an inward rectification property in neuropathic pain.
Similar rectification of the AMPA receptor mediated responses in ACC neurons of rats has been reported after peripheral inflammation with hindpaw CFA injection .
Postsynaptic NMDA NR2B receptor
In an animal model of arthritic pain, it has been reported that inflammation increased phosphorylation but not up-regulation of NMDA NR1 proteins in the central amygdale . In parallel, NMDA receptor mediated responses are also enhanced.
Sensitivity to inhibition by protein kinase M zeta (PKMζ) inhibitor ZIP
5. Biochemical markers
Membrane GluR1 expression
The trafficking of AMPA receptor subunits has been proposed to contribute to synaptic plasticity underlying hyperalgesia [48–50]. We investigated the distribution of AMPA receptor subunits in the ACC after nerve ligation. We found that induction of neuropathic pain by nerve ligation was associated with an increase in the abundance of the GluR1 subunits in the membrane fraction and a corresponding decrease in the levels in the cytosolic fraction. In contrast, nerve ligation had no effect on the intracellular distribution of GluR2/3 subunits in ACC neurons . The data show that AMPA receptor GluR1 subunit is redistributed in ACC neurons as a result of nerve injury.
In rats with CFA inflammation, Bie et al reported that AMPA GluR1 in the synapsome preparation of the ACC neurons from rats with CFA injection showed significant increases, suggesting that synaptic AMPA GluR1 is significantly increased .
Phosphorylation of GluR1
The phosphorylation of GluR1 subunit of AMPA receptors is critical for synaptic expression of the receptors, their channel properties, and synaptic plasticity [51–53]. We tested the phosphorylation levels of GluR1 subunit at the PKA phosphorylation site (Ser 845) in the ACC of the mice with nerve ligation. We found that the phosphorylation levels of GluR1 were significantly increased in the ACC after nerve injury. The data indicate that the nerve injury can increase the phosphorylation levels of GluR1 through the PKA signaling pathway.
Upregulation of PKMζ as an marker
6. In vivo electrophysiological as direct evidence for chronic pain
7. Long-term structural changes
It has been known that learning related plasticity requires transcriptional and translational processing and triggers long-term structural changes in individual synapses . Considering wide-spreading neuronal plasticity happens in the central nervous system after a peripheral injury, it is expected to find long-term changes in brain areas related to chronic pain. The well known cortical reorganization of somatosensory cortex was reported in monkeys with amputated arms. Recently, in patients with chronic pain such as chronic back pain, loss of cortical areas has been reported [7, 57].
In animal models of inflammatory pain or chronic pain, it has been reported that inhibiting macromolecular synthesis is analgesic . Structural or synaptic changes after nerve injury have also been reported in cortical areas [59, 60]. Metz et al reported that layer 2/3 pyramidal neurons in acute slices of the contralateral medial prefrontal cortex (mPFC) in the rat spared nerve injury model of neuropathic pain showed morphological differences between the mPFC of injured and sham-operated animals . Basal dendrites of neurons from injured rats are longer and have more branches than their counterparts in sham-operated animals; spine density is also selectively increased in basal dendrites of neurons from injured rats.
8. Imaging ACC activity and spike recording in experimental animals
Electrophysiological recordings of sensory induced unit responses from cortical neurons is another direct measure of injury induced cortical changes. The use of responsive threshold, the measurement of receptive field, and changes in the magnitude of nociceptive responses are good indexes for injury related cortical plasticity. It is likely that heterogeneous populations of cells are likely found. For example, in the amygdala, Neugebauer and Li reported (2002) that amygdala neurons showed differential sensitization (measured by spike activities) to sensory afferent inputs in a model of arthritic pain .
In addition to spike recordings, recent studies using whole-cell patch-clamp recordings from adult ACC neurons found that many of ACC neurons are responsive to peripheral nociceptive stimulation. Whole-cell patch-clamp recording offer better sensitivity for detecting possible changes in chronic pain, and evaluate the possible analgesic effects of drugs .
Recent several studies have reported brain activation in awake rats using the imaging technique . In this novel approach, Becerra et al (2010) performed fMRI in trained, acclimated, awake rats . The new approach avoids the potential complicating effects of anesthesia. Differing from experiments in humans, animal needs to be kept under anesthesia state to avoid the movement. Among many cortical areas, they reported that ACC, somatosensory cortexes and IC are activated. This approach can be effectively used for evaluating effects of new drugs on pain in awake animals.
Examples how cortical endpoints can be used
It is known that injury triggers molecular and cellular changes in different parts of the brains. Depending on the specific regions of the brain, these neurobiological changes may contribute to different aspects of pain, such as learning and memory, anxiety, unpleasantness and attention. Although some of these changes can be observed at behavioral levels (i.e., reduced latency to withdrawal; or enhanced responses to noxious stimuli), some are difficult to be studied at behavioral level. One good example to use the cortical endpoints is to evaluate the effects of new drugs in spinal cord injury induced pain. It is commonly reported in patients with spinal cord injury that they suffer long-lasting neuropathic pain caused by the injury. However, in animal models of spinal cord injury, it is impossible to evaluate the drug's analgesic effect using behavioral tests. Using the proposed cortical endpoints, I propose that these cortical endpoints can be used. For example, activation of various IEGs in the pain-related cortex such as ACC can be used to evaluate early activation, and measuring glutamate mediated responses and biochemical markers can be used to evaluate enhanced transmission during chronic pain induced by spinal cord injury. The drugs that inhibited or erased cortical makers may be potentially useful for treating spinal cord injury related chronic pain in patients.
The same endpoints can be used to evaluate drugs that acting at peripheral or spinal mechanisms. In additional behavioral responses, cortical endpoints can be measured before and after drug application. Drugs that reduce peripheral or spinal sensitization or potentiation should reduce activation of cortical markers. The cortical measurement will help to determine if behavioral inhibition is due to pure inhibition of motor neurons that are required for sensitized withdrawal responses in chronic pain conditions. There are some limitations of using these proposed cortical indexes to study 'pain' in animals. It is important to perform additional experiments to distinguish possible changes in these cortical indexes that are important for pain-related memory but not pain itself. Considering that cortical neurons are often activated in different situations, it is not an easy task if the injury is also located within the brain. The use of selective gene-manipulated mice or pharmacological inhibitors may help to address some of these concerns.
In summary, recent basic neurobiological investigations of physiological and pathological mechanisms of pain and chronic pain provide critical information for our understanding of long-term plastic changes in cortical areas. These cortical changes that persisted during the course of chronic pain can be used a valuable index to measure 'pain' in animals. The combined use of these neurobiological indexes, together with or without behavioral motor withdrawal responses, will greatly facilitate our searching for new drugs, and also help us to understand why some of current pain medicine does not work in some clinical conditions.
I would like to thank Dr. Jennings Worley at Vertex Pharmaceuticals LLC for early discussions of cortical plasticity as the endpoint measurements of chronic pain, and Emily England and Morgan Zhuo for the help with writing and citation. This work was supported by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, Canada Research Chair, CIHR84256 and CIHR66975 to Dr. Min Zhuo.
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