Molecular Events Involved in Spinal Hyperexcitability

16 May

Molecular Events Involved in Spinal Hyperexcitability (Central Sensitization) A complex pattern  of events takes place in the spinal cord that changes sen- sitivity of spinal  nociceptive  processing  involving  pre-  and  post-synaptic mechanisms.  (1) During peripheral  inflammation  the spinal release of me- diators  such as glutamate, SP, neurokinin  A and CGRP from nociceptors  is increased  (Schaible 2005). (2) Spinal cord  neurons  are sensitized  by acti- vation  of NMDA receptors,  and  this process is supported  by activation  of metabotropic  glutamate, NK-1 and CGRP receptors, and brain-derived  neu- rotrophic  factor  plays a role as well (Woolf and  Salter 2000). Antagonists to the NMDA receptor  can prevent  central  sensitization  and reduce estab- lished hyperexcitability (Fundytus 2001). Antagonists at NK-1 and CGRP re- ceptors  attenuate  central  sensitization.  Ablation of neurons  with NK-1 re- ceptors  was shown to abolish central  sensitization  (Khasabov et al. 2002).

Important molecular steps of sensitization  are initiated  by Ca2+  influx into cells through  NMDA receptors  and voltage-gated calcium channels  (Woolf

and Salter 2000). Ca2+ activates Ca2+–dependent  kinases that e.g. phospho- rylate NMDA receptors.  (3) The subunits  NR1 and GluR1 of glutamate  re-

ceptors show an up-regulation  of the protein and an increase of phosphory- lation (also of the NR2B NMDA receptor  subunit)  thus enhancing  synaptic glutamatergic  transmission.  First changes  appear  within  10 min  after  in-

duction  of inflammation  and  correlate  well with behavioural  hyperalgesia (Dubner  2005). (4) Expression of genes that  code for neuropeptides is en- hanced. In particular,  increased gene expression of opioid peptides (dynor- phin and enkephalin) have become known, suggesting that inhibitory mech-

anisms are up-regulated  for compensation.  However, dynorphin  has both an inhibitory action via κ receptors and excitatory actions involving NMDA re- ceptors.  (5) Other  mediators  such as spinal  prostaglandins  and  cytokines modify central hyperexcitability. As mentioned  above, sources of these me-

diators  are neurons,  glia cells, or both (Marchand  et al. 2005; Watkins and Maier 2005). Spinal actions of prostaglandins  include increase of transmitter release (cf. Vanegas and Schaible 2001), inhibition  of glycinergic inhibition (Ahmadi et al. 2002) and direct depolarization  of dorsal horn neurons (Baba et al. 2001).

In the case of neuropathic  pain, loss of inhibition  is being discussed as a major mechanism  of spinal hyperexcitability.  Reduced inhibition  may be produced  by loss of inhibitory interneurons through excitotoxic actions and apoptosis (Dubner 2005, see, however, Polgár et al. 2004).

Descending Inhibition and Facilitation


Periaqueductal Grey and Related Brain Stem Nuclei

From brain  stem nuclei, impulses  “descend”  onto  the spinal  cord  and  in- fluence the transmission  of pain signals at the dorsal horn  (cf. Fields and Basbaum 1999; Ossipov and Porreca 2005). Concerning  descending  inhibi- tion, the periaqueductal  grey matter (PAG) is a key region. It projects to the rostral ventromedial  medulla (RVM), which includes the serotonin-rich nu- cleus raphe magnus (NRM) as well as the nucleus reticularis gigantocellularis pars alpha and the nucleus paragigantocellularis  lateralis (Fields et al. 1991), and it receives inputs from the hypothalamus, cortical regions and the limbic system (Ossipov and Porreca 2005). Neurons in RVM then project along the dorsolateral  funiculus (DLF) to the dorsal horn.  Exogenous opiates imitate endogenous  opioids and induce analgesia by acting upon PAG and RVM in addition to the spinal dorsal horn (Ossipov and Porreca 2005). RVM contains so-called on- and off-cells. Off-cells are thought to exert descending inhibition of nociception, because whenever their activity is high there is an inhibition of nociceptive transmission,  and because decreases in off-cell firing correlate with increased nociceptive transmission. On-cells instead seem to facilitate no- ciceptive mechanisms at the spinal dorsal horn. Thus, RVM seems to generate antinociception  and facilitation of pain transmission  (Gebhart 2004; Ossipov and Porreca 2005). Ultimately, spinal bulbospinal loops are significant in set- ting the gain of spinal processing (Porreca et al. 2002; Suzuki et al. 2002).

A particular form of descending inhibition of wide dynamic range (WDR) neurons is the “diffuse noxious inhibitory control” (DNIC). When a strong nox- ious stimulus is applied to a given body region, nociceptive neurons with input from that body region send impulses to structures located in the caudal medulla (caudal to RVM), and this triggers a centrifugal inhibition (DNIC) of nocicep- tive WDR neurons located throughout the neuraxis (Le Bars et al. 1979a, b).


Changes of Descending Inhibition and Facilitation During Inflammation

In models of inflammation, descending inhibition predominates  over facilita- tion in pain circuits with input from the inflamed tissue, and thus it attenuates primary hyperalgesia. This inhibition  descends from RVM, LC and possibly other supraspinal  structures,  and spinal serotonergic (from RVM) and nora- drenergic (from LC) mechanisms are involved. By contrast, descending facilita- tion predominates over inhibition in pain circuits with input from neighbour- ing tissues, thus facilitating secondary hyperalgesia. Reticular nuclei located dorsally to RVM also participate in facilitation of secondary hyperalgesia. Le-

sion of these nuclei completely prevents secondary hyperalgesia (Vanegas and

Schaible 2004).

In the RVM, excitatory amino acids mediate descending modulation in re- sponse to transient noxious stimulation and early inflammation, and they are involved in the development of RVM hyperexcitability associated with persis- tent pain (Heinricher  et al. 1999; Urban and Gebhart 1999). As in the spinal cord, increased gene and protein expression and increased phosphorylation of NMDA and AMPA receptors take place in RVM (Dubner 2005; Guan et al. 2002).

A hypothesis is that messages from the inflamed tissue are amplified and relayed until they reach the appropriate brain stem structures.  These in turn

send descending impulses to the spinal cord, dampen  primary hyperalgesia and cause secondary hyperalgesia. It is also possible that the “secondary neu- ronal pool” becomes hyperexcitable as a result of intraspinal mechanisms and

that  descending  influences mainly play a contributing,  yet significant, role in secondary hyperalgesia. Thus, during inflammation  descending influences are both  inhibitory  and  facilitatory, but  the mix may be different  for pri-

mary and secondary hyperalgesia and may change with time (Vanegas and

Schaible 2004).


Changes of Descending Inhibition and Facilitation During Neuropathic Pain

Peripheral nerve damage causes primary hyperalgesia and allodynia that seem to develop autonomously at the beginning but need facilitation from RVM for their maintenance. CCKB receptor activation, as well as excitation of neurons that express μ-opioid receptors in RVM, is essential for maintaining hyperex- citability in the primary neuronal pool (Porreca et al. 2002; Ossipov and Porreca

2005; Vanegas and Schaible 2004). “Secondary neuronal pools” are subject to a descending inhibition that is induced by the nerve damage and stems from the PAG. In contrast  with inflammation,  facilitation prevails in the primary while inhibition prevails in the secondary pool (Vanegas and Schaible 2004).

Generation of the Conscious Pain Response in the Thalamocortical System

The conscious pain response is produced by the thalamocortical system (Fig. 2). Electrophysiological data and brain imaging in humans have provided insights into which parts of the brain are activated upon noxious stimulation. As pointed out earlier, pain is an unpleasant sensory and emotional experience, and these different components of the pain response are produced by different networks. The analysis of the noxious stimulus for its location, duration  and intensity is the sensory-discriminative aspect of pain. This is produced  in the lateral thalamocortical  system consisting of relay nuclei in the lateral thalamus and

the areas SI and SII in the post-central gyrus. In these regions innocuous and noxious stimuli are discriminated (Treede et al. 1999).

The second component of the pain sensation is the affective aspect, i.e. the noxious stimulus is unpleasant and causes aversive reactions. This component is produced in the medial thalamocortical system, which consists of relay nu- clei in the central and medial thalamus, the anterior  cingulate cortex (ACC), the insula and the prefrontal cortex (Treede et al. 1999; Vogt 2005). These brain structures  are part of the limbic system, and the insula may be an interface of the somatosensory  and the limbic system. Even when destruction  of the somatosensory cortex impairs stimulus localization, pain affect is not altered. It should be noted that limbic regions are not only involved in pain processing. In particular the ACC is activated during different emotions including sadness and happiness, and parts of the ACC are also involved in the generation of au- tonomic responses (they have projections to regions that command autonomic output  systems). Other cingulate regions are involved in response selection (they have projections to the spinal cord and the motor cortices) and the ori- entation of the body towards innocuous and noxious somatosensory stimuli. A role of the ACC in the process of memory formation/access  has also been put forward (Vogt 2005).


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