Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus

Abstract

Despite being one of the first-choice analgesics for chronic neuropathic pain, gabapentin sometimes fails to provide analgesia, but the mechanisms for this lack of efficacy is unclear. Rats with nerve injury including L5-L6 spinal nerve ligation (SNL) respond uniformly and well to gabapentin, but many of these studies are performed within just a few weeks of injury, questioning their relevance to chronic neuropathic pain. In this study, intraperitoneal gabapentin showed a time-dependently reduction in antihypersensitivity after SNL, associated with downregulation of astroglial glutamate transporter-1 (GLT-1) in the locus coeruleus (LC). Consistently, SNL also time-dependently increased basal but masked gabapentin-induced noradrenergic neuronal activity in the LC. In rats 2 weeks after SNL, knock-down of GLT-1 in the LC reduced the antihypersensitivity effect of gabapentin. In rats 8 weeks after SNL, increasing GLT-1 expression by histone deacetylase inhibitor valproate restored the antihypersensitivity effect of gabapentin, associated with restored gabapentin-induced noradrenergic neuronal activity in the LC and subsequent spinal noradrenaline release. Knock-down of GLT-1 in the LC reversed the effect of valproate to restore gabapentin-induced antihypersensitivity. In addition, the antihypersensitivity effect of the intrathecal α2-adrenoceptor agonist clonidine also decreased with time after SNL injury. These results suggest that downregulation of GLT-1 in the LC and reduced spinal noradrenergic inhibition contribute to impaired analgesic efficacy from gabapentin in chronic neuropathic pain and that valproate can rescue this impaired efficacy.

The influence of aging and duration of nerve injury on the antiallodynic efficacy of analgesics in laboratory mice

“…The pregabalin observations are, to the best of our knowledge, a novel finding. Perhaps the most relevant published finding to the current experiment is the report by Kimura et al 11 regarding changes in gabapentin efficacy over time after nerve injury in rats. They demonstrated that the peak of gabapentin's effectiveness in reversing spinal nerve ligation-induced mechanical sensitivities on the Randall–Selitto test was at 1 to 2 weeks after surgery, with significant reductions observed starting at 4 weeks after surgery and no differences from saline by 8 weeks after surgery.…”

“…The mechanism underlying the decreasing analgesic efficacy was related to downregulation over time of glutamate transporter-1 (GLT-1) in the locus coeruleus and thus reduced spinal noradrenergic inhibition. 11 It is unclear whether such a mechanism has direct relevance to the present observations because the 2 studies differed in their subjects (mice vs rats), drug (pregabalin vs gabapentin), injury (SNI vs spinal nerve ligation), and, most importantly, time after nerve injury (10 months vs 10 weeks).…”

Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice

“…For instance, only those patients able to tolerate short- and long-term side effects had a significant pain relief (Putzke et al., 2002) and also, gabapentin lose efficacy in patients reporting neuropathic pain symptoms for more than 6 months (Ahn et al., 2003). In parallel with clinical evidences, gabapentin and pregabalin sometimes fail to provide analgesia in animal models (M’Dahoma et al., 2014; Kimura et al., 2016). Thus, the results obtained regarding gabapentinoid efficacy are controversial, and the use of σ1R antagonist may be an emerging suitable alternative to attenuate CNP development.…”

Heme oxygenase-1 inducer and carbon monoxide–releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice

“…Although gabapentinoids are believed to exert antinociceptive effects mainly through the Ca 2+ channel α 2 δ 1 subunit, serotonin- or noradrenaline-mediated descending modulation might be involved in the effects of gabapentinoids. 9 , 24 Previous studies have shown that gabapentin activates the interleukin-10/HO-1 signaling pathway and enhances morphine's antinociceptive effects. 3 , 27 HO-1 inhibitors partially block the effect of gabapentin on morphine.…”