Experimental Central Post-stroke Pain: Thalamic Nuclear Localization, Underlying Mechanisms And Drug Effects

As an intractable neuropathic pain, central post-stroke pain (CPSP) which results indisability and interferes with rehabilitation quality of daily life is one of the mosttroublesome sequelae of stroke and can be caused by a primary lesion affecting the centralsomatosensory system following both ischemic stroke and intracerebral hemorrhage.Although lesions at any level of the spinothalamocortical pathways from the medulla tothe cortex may give rise to a CPSP syndrome, CPSP induced by thalamic lesion (thalamicpain syndrome) is more common and was first described100years ago. The distribution,onset time and the clinical characteristics of CPSP vary substantially between patients dueto the localisation of the lesion in the central nerve system. Antidepressants and anticonvulsants have been frequently recommended as first line clinical drugs fortreatment of neuropathic pain in general, however a large proportion of patients are leftwith insufficient pain relief due to limited improvement. Since the scarce of well-designedclinical trials for evaluation of pharmacological efficacy of antidepressants andanticonvulsants, the experience of pharmacological treatment for patients with CPSP arestill limiting, even leading to drug abuse. Furthermore, the underlying mechanisms ofCPSP remain largely unknown as well due to lack of experimental studies in animalmodels of CPSP. In2009, Wasserman and Koeberle first describe a rat model of CPSPinduced by intra-thalamic collagenase (ITC) microinjection, while whether the model isvalid and stable remains unclear due to the absence of further research. In present study,we quantitatively refined the sensory abnormalities of CPSP following ITC microinjectionand analysed the relationship between the localized hemorrhagic lesion and developmentof central post-stroke pain hypersensitivity following intra-thalamic collagenase. Thepotential underlying mechanism of CPSP was explored. In addition, the effcacy, safety,and tolerability of gabapentin for pain relief with this rat model were also evaluated.The following are the main results:1. The behavioral evulation and thalamic nuclear localization of experimentalCPSP following thalamic hemorrhageAmong16rats subjected to intra-thalamic collagenase IV (ITC) injection,9(56%)exhibited a significant decrease of paw withdrawal mechanical threshold in bilateral hindpaws at7day post injection, and the mechanical pain hypersensitivity persisted28daysafter ITC injection. No significant changes were identified in thermal pain sensitivity ofbilateral hind paws. Out of16rats that received ITC injection,7(44%) showed nosignificant changes in either mechanical or thermal pain sensitivity compared to the basalvalues. All the na ve rats and rats received intra-thalamic saline (ITS) injection had nochanges in either mechanical or thermal pain sensitivity. Histological analysis revealedthat the hemorrhagic lesions of9rats with mechanical pain hypersensitivity were mainlyconfined to the ventroposterior lateral nucleus of the thalamus (VPL), the ventroposteriormedial nucleus of the thalamus (VPM), the medial lemniscus (ml) and/or the posterior thalamic nucleus (Po). While the sites of the hemorrhagic lesion of the7rats withoutmechanical pain hypersensitivity involved the internal capsule (n=3), middle one third ofthe thalamus (n=1), the lateral and medial geniculate bodies (n=3). The motorcoordination performances of rats that developed CPSP following ITC were affectedsignificantly. In the Open field test, both the total traveling distance and time spent in thecentral area of rats with central post–stroke pain hypersensitivity decerased in comparingwith na ve rats.2. The role of SDF-1α/CXCR4singnaling in the development of CPSP followingthalamic hemorrhage.At7days post ITC injection, a number of activated microglia/macrophages andastrocytes were present in the area of hemorrhagic lesion. Simultaneously intra-thalamicinjection of AMD3100, a selective CXCR4antagonist, inhibited the activation ofmicroglia/macrophages and astrocytes induced by ITC, and the bilateral mechanical painhypersensitivity following ITC injection was also partially reversed by AMD3100.Unilateral intra-thalamic SDF-1injection induced accumulation of activated astrocyte inthalamus and bilateral mechanical pain hypersensitivity. The mechanical painhypersensitivity could be identified on3days post injection and remained little recovereduntil28days. Intra-thalamic injection of AMD3100significantly inhibited the activationof astrocytes and the bilateral mechanical hypersensitivity induced by SDF-1.3. The pharmacological evulation of gabapentin on the rat model of CPSPfollowing thalamic hemorrhageBoth single and accumulative intraperitoneal administration of gabapentin (1mg/kg)had no significant effect on the mechanical pain hypersensitivity, while two higher doses(10,100mg/kg) of gabapentin reversed bilateral mechanical pain hypersensitivity indose-dependent manner. Although the anti-allodynic effect of the highest dose (100mg/kg)after accumulative administration for14days remained relatively unchanged, the timecourse of anti-allodynic effectiveness shortened. Compared to single administration, theanti-allodynic effect of10mg/kg of GBP after accumulative i.p. administration for14days disappeared. Gabapentin (100mg/kg, the highest dose used in the present experiment) did not affect the motor coordination performance and locomotor activities of ratsdeveloped mechanical pain hypersensitivity following ITC.Conclusions:1) The experimental model of CPSP induced by thalamic hemorrhagic stroke followingITC injection was stable and valid.2) CPSP produced by ITC injection is region specific, and the development ofmechanical pain hypersensitivity was mainly due to the injury of ml-VPL/VPM/Posystem.3) SDF-1/CXCR4signaling system may be involved in the development of CPSPinduced by ITC injection via activation.of glial cells.4) Gabapentin could effectively inhibit the CPSP in dose-dependent manner, while longterm use of gabapentin may result in tolerance for relief of CPSP. All of these studiesindicated that both the dose and time course of gabapentin should be considered forclinician in CPSP management.