Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain

The saphenous partial ligation (SPL) model is a new, easily performed, rodent model of neuropathic pain that consists of a unilateral partial injury to the saphenous nerve. The present study describes behavioral, pharmacological and molecular properties of this model. Starting between 3 and 5 days after surgery, depending on the modality tested, animals developed clear behaviors indicative of neuropathic pain such as cold and mechanical allodynia, and thermal and mechanical hyperalgesia compared with naive and sham animals. These pain behaviors were still present at 1 month. Signs of allodynia also extended to the sciatic nerve territory. No evidence of autotomy or bodyweight loss was observed. Cold and mechanical allodynia but not thermal and mechanical hyperalgesia was reversed by morphine (4 mg/kg i.p.). The cannabinoid receptor agonist WIN 55,212-2 (5 mg/kg i.p.) improved signs of allodynia and hyperalgesia tested except for mechanical hyperalgesia. Gabapentin (50 mg/kg i.p.) was effective against cold and mechanical allodynia but not hyperalgesia. Finally, amitriptyline (10 mg/kg i.p.) failed to reverse allodynia and hyperalgesia and its administration even led to hyperesthesia. Neurobiological studies looking at the expression of mu opioid receptor (MOR), cannabinoid CB(1) and CB(2) receptors showed a significant increase for all three receptors in ipsilateral paw skin, L3-L4 dorsal root ganglia and spinal cord of neuropathic rats compared with naive and sham animals. These changes in MOR, CB(1) and CB(2) receptor expression are compatible with what is observed in other neuropathic pain models and may explain the analgesia produced by morphine and WIN 55,212-2 administrations. In conclusion, we have shown that the SPL is an adequate model that will provide a new tool for clarifying peripheral mechanisms of neuropathic pain in an exclusive sensory nerve.     

Comparison of three models of neuropathic pain in mice using a new method to assess cold allodynia: The double plate technique

The recent identification of receptors sensitive to cold stimuli increased the significance of using mice to study cold allodynia, one of the important features of neuropathic pain. However, commonly used techniques (simple cold plate and acetone technique) may be inappropriate to study cold allodynia in mice because of problems of interpretation. We have developed a new method for assessing aversion to a cold non-noxious stimulus. It consists of calculating the time that mice spend on a non-noxious cold plate during their explorative behavior versus a thermoneutral one. We used three different models of neuropathic pain: chronic constriction injury of the sciatic nerve (CCI), partial sciatic nerve ligation (PSL) and chronic constriction of the saphenous nerve (CCS) with their respective sham groups and naive animals to assess the double plate in comparison to the acetone drop technique. All operated mice displayed cold allodynia with both methods. The response to acetone and the time spent on the cold plate were correlated (r = −0.93) and we also showed that the CCI mice were more sensitive to cold. Pharmacological validation of this technique showed that CCI induced cold allodynia was alleviated by gabapentin. In conclusion, the double plate technique provides a new, relevant method for assessing cold allodynia in mice. The advantages and drawbacks with the other techniques are discussed.     

Bone marrow stromal cells induce changes in pain behavior after sciatic nerve constriction

Peripheral nerve injury, i.e. a single ligature nerve constriction (SLNC), triggers neuropathic pain. Bone marrow stromal cells (MSCs) have been observed to migrate to the injured tissues and mediate functional recovery following brain, spinal cord and peripheral nerve lesions. We have recently shown MSC selective migration to the ipsilateral lumbar (L3-6) dorsal root ganglia (DRGs) after a sciatic nerve SLNC. In this study, we have analyzed the thermal and mechanical sensitivities of animals subjected to a SLNC of the sciatic nerve and an ipsilateral intraganglionic MSC injection, using the von Frey and Choi tests. Control animals were subjected to the nerve lesion either alone or followed by the administration of phosphate-buffered saline (PBS) or bone marrow non-adherent mononuclear cells (BNMCs). All the animals were tested both before surgery and after 1, 3, 7, 14, 21, 28 and 56 days. Animals subjected to the sciatic nerve constriction developed ipsilateral mechanical and thermal allodynia already 3 days after the lesion. The allodynic responses were maintained even after 56 days. MSC administration prevented the generation of mechanical allodynia and reduced the number of allodynic responses to cold stimuli. On the contrary, the injection of either PBS or BNMCs could not counteract allodynia. These results suggest that MSCs may modulate pain generation after sciatic nerve constriction. The underlying mechanisms by which MSCs exert their actions on pain behavior need to be clarified.     

Hyperalgesia and increased neuropathic pain-like response in mice lacking galanin receptor 1 receptors

The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+) controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush.The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.     

Effects of 17β-estradiol on glucose transporter 1 expression and endothelial cell survival following focal ischemia in the rats

To characterize various animal models of neuropathic pain, we compared three previously developed rat models using the same behavioral testing methods. These models involve: (1) chronic constriction injury by loose ligation of the sciatic nerve (CCI); (2) tight ligation of the partial sciatic nerve (PSL); and (3) tight ligation of spinal nerves (SNL). Comparisons were made for the time course of behavioral signs representing various components of neuropathic pain as well as for the effects of surgical sympathectomy. In general, all three methods of peripheral nerve injury produced behavioral signs of both ongoing and evoked pain with similar time courses. However, there was a considerable difference in the magnitude of each pain component between models. Signs of mechanical allodynia were largest in the SNL injury and smallest in the CCI model. On the other hand, behavioral signs representing ongoing pain were much more prominent in the CCI model than in the other two. Although the behavioral signs of neuropathic pain tended to decrease after sympathectomy in all three models, the change was most evident in the SNL model. The results of the present study suggest that the three rat models tested have contrasting features, yet all are useful neuropathic pain models, possibly representing different populations of human neuropathic pain patients.     

Local application of capsaicin alleviates mechanical hyperalgesia after spinal nerve transection

Whether modulation of C afferent fiber activities could relieve peripheral neuropathic pain was tested. After establishment of neuropathic pain induced by L5 and 6 spinal nerve transection (SNT), the sciatic nerve was treated with 2% capsaicin at the level of the midthigh. Mechanical hyperalgesia (von Frey filaments) was significantly alleviated from 7 days to 4 weeks after capsaicin treatment, but cold allodynia (acetone) was unchanged. Immunohistochemical studies showed a significant increase in the number of calcitonin gene-related peptide (CGRP)-positive neurons, but not TRPV1-positive neurons in intact L4 dorsal root ganglia after SNT. Capsaicin treatment decreased TRPV1- and CGRP-positive neurons in L4 DRG of the treated side, but not the opposite side. These results suggest that local application of capsaicin onto the sciatic nerve can alleviate mechanical hyperalgesia, but not cold allodynia, in a peripheral neuropathic pain model and the pain alleviation may result from a decrease of TRPV1- and CGRP-positive sensory neurons of which fibers pass through the sciatic nerve.     

Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat.

Recent evidence has shown that activation of the N-methyl-D-aspartate receptor mediates the thermal hyperalgesia produced in a model of neuropathic pain. As the acute nociceptive effects of N-methyl-D-aspartate have been reported to be mediated through production of nitric oxide and activation of soluble guanylate cyclase, these experiments were designed to determine whether the thermal hyperalgesia produced in a rat model of neuropathic pain is also mediated through the production of nitric oxide and activation of soluble guanylate cyclase. Loose ligation of the sciatic nerve with chromic gut sutures, but not bilateral sham rats, demonstrated evidence of a marked thermal hyperalgesia on day 3 post-surgery. In bilateral sham rats, intrathecal administration of either an alternate substrate for nitric oxide synthase, NW-nitro-L-arginine methyl ester, or the soluble guanylate cyclase inhibitor, Methylene Blue, did not produce any change in thermal nociceptive withdrawal latencies. These same treatments blocked the thermal hyperalgesia in rats with chromic gut ligatures for a period of 2 and 4 h, respectively. These results suggest that a sustained production of nitric oxide and subsequent activation of soluble guanylate cyclase in the lumbar spinal cord mediate the thermal hyperalgesia produced in a model of neuropathic pain in the rat.     

Calcitonin gene-related peptide, substance P and protein gene product 9.5 immunoreactive axonal fibers in the rat footpad skin following partial sciatic nerve injuries

Chronic constriction injury (CCI) and partial ligation (PSNL) of the sciatic nerve induce a similar neuropathic pain syndrome in rats. We examined calcitonin gene-related peptide (CGRP), substance P (SP) and protein gene product (PGP) 9.5 immunoreactive (IR) axons in the footpad skin after the two types of injury. Four and 14 days after CCI, CGRP- and SP-IR axons in the ipsilateral footpad skin disappeared in most rats, but in one third, sparse CGRP- and SP-IR fibers remained. PGP-IR axons dramatically decreased, but some thick fiber fascicles appeared. At the ultrastructural level, these PGP-IR thick fiber fascicles were characterized as unmyelinated axons surrounded by non-IR Schwann cells. Some of these axons were swollen and irregular in shape. In contrast, 4 days after PSNL, CGRP-, SP-, and PGP-IR axons in the ipsilateral footpad skin were present, though significantly reduced in density, in all rats, and by 14 days all IR fiber densities in the footpad skin partially recovered. The loss of CGRP and SP axons in the footpad skin of the CCI model suggests that sensory nerves containing neuropeptides are not essential in transducing stimuli applied to the footpad skin into neuropathic pain, but the abnormal PGP-IR unmyelinated axons in thick fiber fascicles might play a role. The partial loss and rapid recovery of IR axons in the footpad skin after PSNL shows that the two injury models, causing similar behaviors, are associated with very different patterns of cutaneous innervation at the time when the pain syndrome is well developed.     

Optical coherence tomography reveals in vivo cortical plasticity of adult mice in response to peripheral neuropathic pain

We examined neural plasticity in mice in vivo using optical coherence tomography (OCT) of primary somatosensory (S1) and motor (M1) cortices of mice under the influence of sciatic nerve chronic constriction injury (CCI), a model of neuropathic pain widely utilized in rats. The OCT system used in this study provided cross-sectional images of the cortical tissue of mice up to a depth of about 1mm with longitudinal resolution up to 11 microm. This is the first study to evaluate neural plasticity in vivo using OCT. CCI mice exhibited cold allodynia and spontaneous pain behaviors, which are signs of neuropathic pain, 30 days after sciatic nerve ligation, when OCT observation of S1 and M1 cortices was carried out. The scattering intensity of near-infrared light within the hind paw area of S1 and M1 regions in the contralateral hemisphere was significantly higher than in the ipsilateral hemisphere. These CCI-induced increases in scattering intensity within cortical regions associated with the hind paw probably reflect elevated neural activity associated with neuropathic pain. Synapses and mitochondria are believed to have high light scattering coefficients, since they contain remarkably high concentrations of proteins and complicated membrane structure. Number densities of mitochondria and synapses are known to increase in parallel with increases in neural activity. Our findings thus suggest that neuropathic pain gives rise to neural plasticity within the hind paw area of S1 and M1 contralateral to the ligated sciatic nerve.     

Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain.

Chronic constriction injury of the sciatic nerve and lumbar L5 and L6 spinal nerve ligation provide animal models for pain syndromes accompanying peripheral nerve injury and disease. In the present study, we evaluated changes in brain-derived neurotrophic factor (BDNF) immunoreactivity in the rat L4 and L5 dorsal root ganglia (DRG) and areas where afferents from the DRG terminates (the L4/5 spinal cord and gracile nuclei) in these experimental models of neuropathic pain. Chronic constriction injury induced significant increase in the percentage of small, medium and large BDNF-immunoreactive neurons in the ipsilateral L4 and L5 DRG. Following spinal nerve ligation, the percentage of large BDNF-immunoreactive neurons increased significantly, and that of small BDNF-immunoreactive neurons decreased markedly in the ipsilateral L5 DRG, while that of BDNF-immunoreactive L4 DRG neurons of all sizes showed marked increase. Both chronic constriction injury and spinal nerve ligation induced significant increase in the number of BDNF-immunoreactive axonal fibers in the superficial and deeper laminae of the L4/5 dorsal horn and the gracile nuclei on the ipsilateral side.Considering that BDNF may modulate nociceptive sensory inputs and that injection of antiserum to BDNF significantly reduces the sympathetic sprouting in the DRG and allodynic response following sciatic nerve injury, our results also may suggest that endogenous BDNF plays an important role in the induction of neuropathic pain after chronic constriction injury and spinal nerve ligation. In addition, the increase of BDNF in L4 DRG may contribute to evoked pain which is known to be mediated by input from intact afferent from L4 DRG following L5 and L6 spinal nerve ligation.     

Interleukin-17 levels in rat models of nerve damage and neuropathic pain

In the present study, we assessed IL-17 levels at 3 and 8 days following various forms of injuries to the sciatic nerve and related the cytokine levels to the pain behaviors associated with the injuries. The four experimental models employed were chronic constriction injury (CCI), partial sciatic ligation (PSL), complete sciatic transection (CST) and perineural inflammation (Neuritis). Behavior withdrawal thresholds for mechanical stimulus and withdrawal latency for thermal stimulation were used to measure mechanical allodynia and thermal hyperalgesia. IL-17 levels of the affected, contralateral and naïve rats’ sciatic nerve were assessed employing enzyme-linked immunosorbent assay (ELISA). Rats exposed to CCI and Neuritis displayed significant mechanical allodynia and thermal hyperalgesia 3, 5 and 8 days following the procedure, rats exposed to PSL displayed significant mechanical allodynia 5 and 8 days following the procedure and rats exposed to CST developed significant hypoesthesia. Three days following the procedure, IL-17 levels increased significantly compared to naïve rats only in the PSL model. Eight days following the procedure, IL-17 levels in nerves exposed to CCI, CST, PSL and Neuritis were significantly elevated compare to intact nerve levels. It is likely that IL-17 has a limited role in the acute phase of nerve injury and the associated acute pain, but may have a role in later phases of the processes of the development of neuropathic pain.     

Glutamate transporter dysfunction associated with nerve injury-induced pain in mice

Dysfunction at glutamatergic synapses has been proposed as a mechanism in the development of neuropathic pain. Here we sought to determine whether peripheral nerve injury-induced neuropathic pain results in functional changes to primary afferent synapses. Signs of neuropathic pain as well as an induction of glial fibrillary acidic protein in immunostained spinal cord sections 4 days after partial ligation of the sciatic nerve indicated the induction of neuropathic pain. We found that following nerve injury, no discernable change to kinetics of dl-α-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA) or N-methyl-d-aspartate receptor (NMDAR)-mediated evoked excitatory postsynaptic currents (eEPSCs) could be observed in dorsal horn (lamina I/II) neurons compared with those of na?ve mice. However, we did find that nerve injury was accompanied by slowed decay of the early phase of eEPSCs in the presence of glutamate transporter inhibition by the competitive nontransportable inhibitor dl-threo-β-benzyloxyaspartic acid (TBOA). Concomitantly, expression patterns for the two major glutamate transporters in the spinal cord, excitatory amino acid transporters (EAAT) 1 and EAAT2, were found to be reduced at this time (4 days postinjury). We then sought to directly determine whether nerve injury results in glutamate spillover to NMDARs at dorsal horn synapses. By employing the use-dependent NMDAR blocker (±)MK-801 to block subsynaptic receptors, we found that although TBOA-induced spillover to extrasynaptic receptors trended to increased activation of these receptors after nerve injury, this was not significant compared with na?ve mice. Together, these results suggest the development of neuropathic pain involves subtle changes to glutamate transporter expression and function that could contribute to neuropathic pain during excessive synaptic activity.     

Comparison of sympathetic sprouting in sensory ganglia in three animal models of neuropathic pain

Sympathetic postganglionic fibers sprout in the dorsal root ganglion (DRG) after peripheral nerve injury. Therefore, one possible contributing factor of sympathetic dependency of neuropathic pain is the extent of sympathetic sprouting in the DRG after peripheral nerve injury. The present study compared the extent of sympathetic sprouting in the DRG as well as in the injured peripheral nerve in three rat neuropathic pain models: (1) the chronic constriction injury model (CCI); (2) the partial sciatic nerve ligation injury model (PSI); and (3) the segmental spinal nerve ligation injury model (SSI). All three methods of peripheral nerve injury produced behavioral signs of ongoing and evoked pain with some differences in the magnitude of each pain component. The density of sympathetic fibers in the DRG was significantly higher at all examined postoperative times than controls in the SSI model, while it was somewhat higher than controls only at the last examined postoperative time (20 weeks) in the CCI and PSI models. Therefore, data suggest that, although sympathetic changes in the DRG may contribute to neuropathic pain syndromes in the SSI model, other mechanisms seem to be more important in the CCI and PSI models at early times following peripheral nerve injury.     

Effects of repeated administered ghrelin on chronic constriction injury of the sciatic nerve in rats

Chronic constriction injury (CCI) is a peripheral mononeuropathic pain model that is caused by an injury to the peripheral nervous system and refractory to available conventional treatment. Mechanisms involved in neuropathic pain are still unclear. Previous studies reveal that proinflammatory cytokines contribute to CCI-induced peripheral nerve pathology. Ghrelin, a novel identified gastric peptide, has been shown to have antinociceptive activity and also anti-inflammatory properties by decreasing proinflammatory cytokines. Therefore, the aim of the present study was to investigate the effects of ghrelin on the CCI and its relationship with proinflammatory cytokines in rats. Wistar rats underwent sciatic nerve ligation to induce CCI fallowed by repeated ghrelin administrations (50 and 100 μg/kg i.p., once daily) for a period of 14 days. Mechanical hyperalgesia was assessed before surgery and at day 14 after CCI. TNF-α, IL-1β and IL-6 were measured in blood and spinal cord. The changes of sciatic nerve was assessed histologically by both light and electron microscopy. Ghrelin attenuated mechanical hyperalgesia, reduced spinal TNF-α and IL-1β levels and enhanced sciatic nerve injury with correlated morphometric recovery. These results indicate that the protective effect by ghrelin in the spinal cord is mediated through the suppression of TNF-α and IL-1β. Thus ghrelin may be a promising peptide in the management of neuropathic pain.     

Implication of spinal protein kinase C in the suppression of morphine-induced rewarding effect under a neuropathic pain-like state in mice

We previously demonstrated that spinal protein kinase C (PKC) is involved in the development of a neuropathic pain-like state induced by sciatic nerve ligation, and the morphine-induced rewarding effect is attenuated by sciatic nerve ligation in rodents. Here we first investigated whether sciatic nerve injury could change the activity of a conventional PKC (cPKC) and an atypical PKC isoform PKCzeta in the mouse spinal cord. The second experiment was to investigate whether direct inhibition of spinal PKC by intrathecal (i.t.) administration of a specific PKC inhibitor, 2-[8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl]-3-(1-methyl-1H-indole-3-yl)maleimide (RO-32-0432), could affect the rewarding effect induced by morphine following sciatic nerve ligation in mice. We found here that the activities of both cPKC and PKCzeta in the spinal cord were clearly increased following sciatic nerve ligation. Furthermore, i.t. administration of RO-32-0432 reversed a long-lasting pain-like syndrome as indicated by thermal hyperalgesia following sciatic nerve ligation in mice. These data provide direct evidence that activated cPKC and PKCzeta in the spinal cord may contribute to the development and maintenance of neuropathic pain. In the present study, we confirmed that the morphine-induced place preference was significantly suppressed by sciatic nerve ligation. It should be mentioned that i.t. pretreatment with RO-32-0432 significantly reversed the attenuation of morphine-induced rewarding effect following sciatic nerve ligation. These results suggest that activation of PKCs, including cPKC and PKCzeta, within the spinal cord is directly responsible for the attenuation of the morphine-induced rewarding effect under a neuropathic pain-like state following sciatic nerve ligation in mice.     

Helicid alleviates pain and sleep disturbances in a neuropathic pain‐like model in mice

Natural helicid (4‐formylphenyl‐O‐β‐d ‐allopyranoside), a main active constituent from seeds of the Chinese herb Helicia nilagirica, has been reported to exert a sedative, analgesic and hypnotic effect, and is used clinically to treat neurasthenic syndrome, vascular headaches and trigeminal neuralgia. In the current study, mechanical allodynia tests, electroencephalograms, electromyogram recordings and c‐Fos expression in neuropathic pain‐like model mice of partial sciatic nerve ligation were used to investigate the effect of helicid on neuropathic pain and co‐morbid insomnia. Our results showed that helicid at a dose of 100, 200 or 400 mg kg⁻¹ could increase the mechanical threshold by 2.5‐, 2.8‐ and 3.1‐fold for 3 h after administration, respectively. Helicid at 200 and 400 mg kg⁻¹ given at 07:00 hours increased the amount of non‐rapid eye movement sleep in a 3‐h period by 1.27‐ and 1.35‐fold in partial sciatic nerve ligated mice. However, helicid (400 mg kg⁻¹) given at 21:00 hours did not change the sleep pattern in normal mice. Immunohistochemical study showed that helicid (400 mg kg⁻¹) administration could reverse the increase of c‐Fos expression in the neurons of the rostral anterior cingulate cortex and tuberomammillary nucleus, and the decrease of c‐Fos expression in the ventrolateral preoptic area caused by partial sciatic nerve ligation. These results indicate that helicid is an effective agent for both neuropathic pain and sleep disturbances in partial sciatic nerve ligated mice.     

大鼠部分后根损伤诱发机械性痛性感觉异常的交感神经依赖性

建立一个类似临床的后根损伤诱发慢性痛的动物模型,探讨交感神经活动在诱发慢性痛中的作用。在腰5 部分后根结扎损伤的方法建立一个后根损伤大鼠模型,观察损伤诱发的慢性痛形成的行为和电生理学特征及交感节后神经元在慢性痛形成中的作用。结果表明：（1） 腰5 部分后根结扎损伤后,损伤侧后肢出现机械性痛性感觉异常,持续约30 天。（2）提前12 天行腰交感神经干和神经节切除术,部分后根损伤侧后肢不出现机械性痛性感觉异常。（3） 腹腔注射肾上腺素能a 受体阻断剂酚妥拉明（4mg/kg）使机械性痛性感觉异常显著降低,维持约30min。（ 4）后根的部分损伤诱发损伤神经21.7%（162/746）的A 类纤维来自背根节细胞的异位放电活动;全身或局部应用去甲肾上腺素可使异常自发电活动产生改变,其中64.1%的（25/39）A 类纤维兴奋,33.3%（13/390 的A 类纤维抑制。提示交感神经参与后根损伤诱发的机械性痛性感觉异常。     

Increased phosphorylated-mu-opioid receptor immunoreactivity in the mouse spinal cord following sciatic nerve ligation

The present study was designed to determine whether a state of neuropathic pain induced by sciatic nerve ligation could alter phosphorylated-mu-opioid receptor-like immunoreactivity in the superficial dorsal horn of the mouse spinal cord. Mice with sciatic nerve ligation exhibited a significant suppression of the morphine-induced antinociception. Under this condition, phosphorylated-mu-opioid receptor-like immunoreactivity was clearly increased on the ipsilateral side in the superficial laminae of the L5 lumbar spinal dorsal horn in nerve-ligated mice. These findings suggest that the phosphorylation of the mu-opioid receptor in the spinal cord under a neuropathic pain-like state may, at least in part, contribute to the reduction in the antinociceptive effect produced by morphine in the mouse.     

Synaptic plasticity in the substantia gelatinosa in a model of chronic neuropathic pain

Chronic neuropathic pain (CNP) is common after peripheral nerve injuries (PNI), but is rather refractory to available anti-pain medication. Advances in neuropathic pain research have identified cellular and molecular cues triggering the onset of neuropathic pain, but the mechanisms responsible for maintenance of chronic pain states are largely unknown. Structural changes such as sprouting of injured A-fibres into the substantia gelatinosa of the dorsal horn in the spinal cord have been proposed to relate to neuropathic pain in partial PNI models. Structural changes in central pain networks may also underlie the more persistent CNP following complete sectioning of a peripheral nerve, because this type of injury results in continuous and spontaneous afferent input to the spinal cord, which can trigger central sensitization. In the present study, the left sciatic nerve was completely sectioned and a 1-cm segment was removed to maintain a chronic pathology, whereas the right sciatic nerve was left intact. Mechanical allodynia was measured up to 84 days after injury, after which synaptic changes were studied in the lumbar substantia gelatinosa. The numbers of larger sized synaptophysin-immunoreactive presynaptic boutons were found to be increased in the substantia gelatinosa ipsilateral to the nerve injury. From these data we conclude that structural synaptic changes within the substantia gelatinosa are present months after complete nerve injury and that this plasticity may be involved in maintaining neuropathic pain states.