Post-stroke pain hypersensitivity induced by experimental thalamic hemorrhage in rats is region-specific and demonstrates limited efficacy of gabapentin

Abstract

Intractable central post-stroke pain (CPSP) is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and changes in mechanical or thermal pain sensitivity in a rat CPSP model with experimental thalamic hemorrhage produced by unilateral intra-thalamic collagenase IV (ITC) injection. Then, we evaluated the efficacy of gabapentin (GBP), an anticonvulsant that binds the voltage-gated Ca2+ channel α2δ and a commonly used anti-neuropathic pain medication. Histological case-by-case analysis showed that only lesions confined to the medial lemniscus and the ventroposterior lateral/medial nuclei of the thalamus and/or the posterior thalamic nucleus resulted in bilateral mechanical pain hypersensitivity. All of the animals displaying CPSP also had impaired motor coordination, while control rats with intra-thalamic saline developed no central pain or motor deficits. GBP had a dose-related anti-allodynic effect after a single administration (1, 10, or 100 mg/kg) on day 7 post-ITC, with significant effects lasting at least 5 h for the higher doses. However, repeated treatment, once a day for two weeks, resulted in complete loss of effectiveness (drug tolerance) at 10 mg/kg, while effectiveness remained at 100 mg/kg, although the time period of efficacious analgesia was reduced. In addition, GBP did not change the basal pain sensitivity and the motor impairment caused by the ITC lesion, suggesting selective action of GBP on the somatosensory system.

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

“…or by a shortened time-course of a single administration at a higher dose (100 mg/kg, i.p.) [20]. These results are evidence of both spatial and temporal changes in the molecular targets of GBP in the CNS of these rats.…”

“…Surgery was performed as described previously [20,33,34]. Rats were anesthetized with chloralose (0.3 g/kg, i.p.…”

“…Nonetheless, gabapentinoids are commonly used to treat other types of In a recent placebo-controlled trial, pregabalin failed to show significant improvement over placebo in patients with CPSP [19]. More recently, we evaluated the anti-allodynic effects of GBP in rats with CPSP hypersensitivity induced by experimental thalamic hemorrhage and found that, although GBP had a dose-dependent anti-allodynic effect following a single systemic administration, the effectiveness was transient, gradually decreasing after repeated administration for 14 days, implying the existence of drug insensitivity [20]. The GBP insensitivity was shown by a decreased maximal possible effect and the shortened timecourse of a single administration at a lower dose (10 mg/ kg, i.p.)…”

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex

“…Mechanical pain sensitivity was measured using von Frey monofilaments as described previously [39,40]. Rats were individually adapted in a plastic chamber placed on a metal mesh floor for 30 min before testing.…”

“…Thermal pain sensitivity was measured as the withdrawal latency of the hind-paws in response to radiant heat stimuli [39,40]. Rats were individually acclimated to a plastic chamber on the surface of a 2-mm thick glass plate for 30 min before testing.…”