Elsevier

Brain Research

Volume 1381, 24 March 2011, Pages 187-201
Brain Research

Research Report
Role of different brain areas in peripheral nerve injury-induced neuropathic pain

https://doi.org/10.1016/j.brainres.2011.01.002Get rights and content

Abstract

Neuropathic pain has been described as the “most terrible of all tortures which a nerve wound may inflict” and arises as a consequence of nerve injury either of the peripheral or central nervous system. Following peripheral nerve injury, a cascade of events in the primary afferents leads to peripheral sensitization resulting in spontaneous nociceptor activity, decreased threshold and increased response to supra-threshold stimuli. A series of molecular changes in spinal cord and brain centers are associated with central sensitization which is responsible for the pain to non-injured extra-territory regions (extraterritorial pain) and contralateral parts (mirror-image pain). The peripheral nerve injury has been reported to induce neuroplastic changes in different brain regions including the anterior cingulate cortex, insular cortex, ventrolateral orbitofrontal area, amygdala, striatum, thalamus, hypothalamus, rostral ventromedial medulla, periaqueductal gray, pons (locus coeruleus), red nucleus, and medulla oblongata. The present review article discusses the involvement of these different brain areas in the development of peripheral nerve injury-induced neuropathic pain.

Introduction

Peripheral nerve injury leads to the development of neuropathic pain that is characterized by sensory abnormalities including stimulus-independent persistent pain or abnormal sensory perception such as hyperalgesia and allodynia (Woolf and Mannion, 1999). The precise mechanisms underlying neuropathic pain and the relationship among different mechanisms are not fully understood. The information regarding the neuropathic pain mechanisms have been largely obtained from animal models of neuropathic pain in which the sciatic nerve or the spinal nerves are intentionally damaged (Jaggi et al., 2011). Severe nerve damage triggers early neuroplastic changes in the brain to contribute to an endogenous feedback inhibition of pain and hence, serves as a beneficial, adaptive mechanism in times of injury. However with time, injury also recruits facilitatory mechanisms in the brain that ultimately sensitize pain transmission neurons in the spinal cord and such mechanisms help in preventing further injury (Millan, 1999). Under certain conditions, such CNS facilitation persists even after the healing of the injury and contributes in central sensitization that drives the neural and behavioral manifestations of chronic pain (Ren and Dubner, 2002).

Peripheral nerve injury is followed by a change in expression of neurotransmitters, neuromodulators, growth factors and neuroactive molecules in primary afferent neurons located in dorsal root ganglion of the spinal cord. These changes in-turn induce sensitization of primary afferents inputs (peripheral sensitization) leading to exaggerated pain perception in an injured tissue or territory innervated by an injured nerve. Apart from the pain hypersensitivity in an injured tissue, neuropathic pain also spreads to the adjacent non-injured extra-territory regions (extraterritorial pain) and contralateral parts (mirror-image pain) (Woolf and Mannion, 1999) indicating the maladaptive changes in neural network in the central nervous system (central sensitization). The induction of central sensitization has been identified at the spinal cord level (dorsal horn neurons, second order neurons) and in the brain regions (third order neurons). A number of reports have suggested the neuroplastic changes in different brain areas that are responsible for central sensitization and behavioral alterations in peripheral nerve injury-induced neuropathic pain (Table 1 and Fig. 1). Deep brain stimulation (DBS) is employed for ameliorating the long standing neuropathic pain in patients, which includes implantation of electrodes deep in the brain regions followed by electrical stimulation. It has been reported that some patients exhibit substantial reduction in pain scores just with the insertion of electrodes in the absence of stimulation (insertional effect) (Hamani et al., 2006). However, the studies have suggested that long-term efficacy of DBS is quite low in long standing neuropathic pain, which otherwise is very efficacious in attenuating nociceptive pain. Instead, motor stimulation is reported to exhibit greater long term efficacy with lesser complications than DBS (Prévinaire et al., 2009). The electrical stimulation of the motor cortex has been shown to induce spinal anti-nociception in the spinal nerve-ligated neuropathic rats involving the rostroventromedial medulla and locus coerulus (Viisanen and Pertovaara, 2010a, Viisanen and Pertovaara, 2010b). Very recently, it has been shown that the spinal cord stimulation mediated analgesic effect involves the anterior cingulate cortex, prefrontal areas, thalamus and parietal association area (Kishima et al., 2010). The up-regulation of about twenty-six genes involved in the regulation of cell cycle, apoptosis, signal transduction and neuroprotection has been documented in different brain areas in a chronic constriction injury (CCI) model (Tang et al., 2009). The subtotal de-cortication has been shown to significantly delay the onset of autotomy in denervated leg. Clinically, cortical reorganization has been demonstrated in patients with chronic neuropathic pain (Vartiainen et al., 2009). Recently, it has been shown that sarcosine, a competitive inhibitor of glycine type 1 transporter, exhibits analgesic as well as anti-neuropathy effects in a spared nerve injury (SNI) model by modulating the spinal cord and the prefrontal cortex circuitry, respectively (Centeno et al., 2009). Intra-brain microinjection of human mesenchymal stem cells has been shown to decrease allodynia in neuropathic mice along with a reduction in the over-activated mRNA levels of the pro-inflammatory IL-1beta and neural beta-galactosidase in the prefrontal cortex (Siniscalco et al., 2010). The present review discusses the involvement of these different brain areas in the development of peripheral nerve injury-induced neuropathic pain.

Section snippets

Anterior cingulate cortex

The anterior cingulate cortex (ACC) is the forebrain structure that plays an important role in regulating the affective and emotional component of physiological as well as pathological pain (Hutchison et al., 1999, Vogt, 2005). The brain imaging and electrophysiological studies have shown that the ACC responds to painful stimuli in humans and animals. Using an elaborate functional magnetic resonance imaging (fMRI), Baliki et al. (2006) found an increased activity in the ACC during phases of

Periaqueductal gray

Periaqueductal gray (PAG) is the gray matter located around the cerebral aqueduct within the tegmentum of the midbrain and plays an important role in the descending modulation of pain and in defensive behavior. The dual role of PAG i.e., descending pain inhibitory and descending pain facilitatory function has been described. The electrical stimulation of the ventral PAG has been shown to produce analgesia in neuropathic pain in rats by inhibiting dorsal horns through the descending pain

Pons

In pons, the locus coeruleus (LC) is the main nucleus involved in pain processing which is located in the dorsal wall of the rostral pons in the lateral floor of the fourth ventricle. The neurons of LC provide the bulk of norepinephrine (NE) found in the CNS, with an elaborate network of ascending and descending projections. Classically, LC has been interpreted as a source of pain inhibition. The numerous studies have indicated that the LC promotes feedback inhibition of pain by activating

Biological targets in therapeutics of neuropathic pain

Both preclinical and clinical studies in the field of neuropathic pain have led to the understanding of its pathobiology which includes complex interrelated pathways leading to peripheral as well as central sensitization. The advancement in the area of pathobiology of neuropathic pain has revealed number of key targets that include sodium channels [Na(v)1.3; Na(v)1.7; Na(v)1.8; Na(v)1.9] (Hains et al., 2006); potassium channels (KATP channels; KCNQ type; Ca2+-activated K+ channels) (Fritch et

Conclusion

The studies from animal models of neuropathic pain has led to the understanding of pathobiology of peripheral neuropathic pain which includes complex interrelated pathways in the periphery as well as in the central nervous system including brain regions. The peripheral nerve injury-induced changes in peripheral afferent input triggers neuroplastic changes in the brain and leads to development of central sensitization which is responsible for wide spread pain perception in non-injured

Acknowledgment

The authors are grateful to the Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting this study and providing technical facilities for the work.

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