국제통증연구학회(IASP)에 따르면, 신경병증성 통증은 정상 조건에서 중추신경계에 유해한 정보를 전달하는 신경계 기능 장애로 특징 지워진다. 이런 통증은 말초 혹은 중추 신경계에 확인 가능한 병변이 있는 질환과 어떠한 신경에도 병변이 없는 상태에서 발생하는 상황으로 나누어 볼 수 있다. 두 가지 상황 모두 장기적이고 만성적인 변화과정을 겪게 되며, 결과적으로 신경계가 부적절하게 적응하여 치유되기 어려운 만성통증 증후군으로 발전할 수 있다. 그러나 이러한 통증 치료는 진단에서부터 치료까지의 과정이 어려운 탓에 현재까지도 특별한 해결방안이 부족한 실정이다. 최근 자기공명영상(fMRI), 양전자방출단층촬영법(PET), 광영상(optical imaging) 등 영상분석기술이 발달함에 따라 통증을 유발할 수 있는 유해 자극에 대한 중추신경계의 반응을 영상화하는 연구가 증가하고 있다. 이러한 영상 기법들을 통해 통증을 해석하고 처리하는 뇌 영역에서 시냅스 간 가소성 변화가 일어나고 있음을 확인하였으며, 신경병증성 통증을 비롯한 만성통증과 학습과의 상호 작용을 이해하는 데 많은 도움을 주고 있다. 본 연구는 병리적 통증의 기전과 통증 자극에 따른 뇌의 구조적, 기능적 변화에 대해 최근까지 밝혀진 연구들을 소개하고자 한다. 만성적 통증의 정의와 발생기전을 되짚고 새로운 연구 동향을 살펴보는 것은 통증을 완화할 수 있는 방안을 강구하는 데 도움이 될 것으로 사료된다.

The present study investigated the participation of D-serine and NR2 in antinociception produced by blockade of central erythropoietin-producing hepatocellular carcinoma (Eph) A4 (EphA4) signaling in rats with trigeminal neuropathic pain. Trigeminal neuropathic pain was modeled in male Sprague-Dawley rats using mal-positioned dental implants. The left mandibular second molar was extracted under anesthesia, and a miniature dental implant was placed to induce injury to the inferior alveolar nerve. Our current findings showed that nerve injury induced by malpositioned dental implants significantly produced mechanical allodynia; additionally, the inferior alveolar nerve injury increased the expression of D-serine and NR2 subunits in the ipsilateral medullary dorsal horn (trigeminal subnucleus caudalis). Intracisternal administration of EphA4-Fc, an EphA4 inhibitor, inhibited nerve injury-induced mechanical allodynia and upregulated the expression of D-serine and NR2 subunits. Moreover, intracisternal administration of D-amino acids oxidase, a D-serine inhibitor, inhibited trigeminal mechanical allodynia. These results show that D-serine and NR2 subunit pathways participate in central EphA4 signaling after an inferior alveolar nerve injury. Therefore, blockade of D-serine and NR2 subunit pathways in central EphA4 signaling provides a new therapeutic target for the treatment of trigeminal neuropathic pain.

The present study investigated the role of spinal glutamate recycling in the development of orofacial inflammatory pain or trigeminal neuropathic pain. Experiments were carried out on male Sprague–Dawley rats weighing between 230 and 280 g. Under anesthesia, a polyethylene tube was implanted in the atlanto-occipital membrane for intracisternal administration. IL-1β-induced inflammation was employed as an orofacial acute inflammatory pain model. IL-1β (10 ng) was injected subcutaneously into one vibrissal pad. We used the trigeminal neuropathic pain animal model produced by chronic constriction injury of the infraorbital nerve. DL-threo-β -benzyloxyaspartate (TBOA) or methionine sulfoximine (MSO) was administered intracisternally to block the spinal glutamate transporter and the glutamine synthetase activity in astroglia. Intracisternal administration of TBOA produced mechanical allodynia in naïve rats, but it significantly attenuated mechanical allodynia in rats with interleukin (IL)-1 β-induced inflammatory pain or trigeminal neuropathic pain. In contrast, intracisternal injection of MSO produced antiallodynic effects in rats treated with IL-1β or with infraorbital nerve injury. Intracisternal administration of MSO did not produce mechanical allodynia in naive rats. These results suggest that blockade of glutamate recycling induced pro-nociception in naïve rats, but it paradoxically resulted in anti-nociception in rats experiencing inflammatory or neuropathic pain. Moreover, blockade of glutamate reuptake could represent a new therapeutic target for the treatment of chronic pain conditions.

Previous clinical studies have demonstrated that gabapentin, a drug that binds to the voltage-gated calcium channel α2δ1 subunit proteins, is effective in the management of neuropathic pain, but there is limited evidence that addresses the participation of glial cells in the antiallodynic effects of this drug. The present study investigated the participation of glial cells in the anti-nociceptive effects of gabapentin in rats with trigeminal neuropathic pain produced by mal-positioned dental implants. Under anesthesia, the left mandibular second molar was extracted and replaced by a miniature dental implant to induce injury to the inferior alveolar nerve. Mal-positioned dental implants significantly decreased the air-puff thresholds both ipsilateral and contralateral to the injury site. Gabapentin was administered intracisternally beginning on postoperative day (POD) 1 or on POD 7 for three days. Early or late treatment with 0.3, 3, or 30 μg of gabapentin produced significant anti-allodynic effect in the rats with mal-positioned dental implants. On POD 9, in the mal-positioned dental implants group, OX-42, a microglia marker, and GFAP, an astrocyte marker, were found to be up-regulated in the medullary dorsal horn, compared with the naive group. However, the intracisternal administration of gabapentin (30 μg) failed to reduce the number of activated microglia or astrocytes in the medullary dorsal horn. These findings suggest that gabapentin produces significant antinociceptive effects, which are not mediated by the inhibition of glial cell function in the medullary dorsal horn, in a rat model of trigeminal neuropathic pain.

Background: We evaluated the effect of ulinastatin on paw withdrawal threshold (PWT), IL-6, and IL-10 in SD rats after spinal nerve ligation (SNL). Methods: Group C received N/S and Group E received ulinastatin IV for three days following SNL. PWT, IL-6, and IL-10 were measured on the 3rd, 5th, and 7th day. Results: Group E showed higher PWT compared to group C. IL-6 was lower in group E than in group C. No differences in IL-10 were observed between group C and group E. Conclusion: Ulinastatin increased the PWT and its effect appears to be involved with IL-6, not IL-10.

Nerve injury can lead to neuropathic pain, which is often resistant to current analgesics and interventional therapeutic methods. Extracellular signal-regulated kinase (ERK) plays important role in the induction of neuropathic pain. We explored the antinociceptive effect of curcumin and its effect on ERK in the spinal cord in the neuropathic pain model of rats induced by chronic constriction injury (CCI) of the sciatic nerve. In injured rats, mechanical allodynia, which is one of characteristics of neuropathic pain developed and the activation of ERK in spinal cord significantly increased compared with control group. However, administration of curcumin (50 mg/kg/day p.o) for 7 days started from one day before the injury prevented the development of mechanical allodynia and increase of ERK phosphorylation. These results indicate that curcumin can be a new therapeutic agent in the treatment of neuropathic pain.