Pretreatment with intrathecal amitriptyline potentiates anti-hyperalgesic effects of post-injury intra-peritoneal amitriptyline following spinal nerve ligation

Abstract

BackgroundAmitriptyline, a tricyclic antidepressant and potent use-dependent blocker of sodium channels, has been shown to attenuate acute and chronic pain in several preclinical modes. The purpose of this study was to investigate whether intrathecal pretreatment with amitriptyline combined with post-injury intra-peritoneal amitriptyline is more effective than post-injury treatment alone on L5 spinal nerve ligation (SNL)-induced neuropathic pain.Methods96 adult male Sprague–Dawley rats were allocated into 4 groups: group S, Sham; group L, L5 spinal nerve Ligation with vehicle treatment; group A, SNL and post-injury intra-peritoneal (Abdominal) amitriptyline twice daily × 3 days; group P, intrathecal Pretreatment with amitriptyline, SNL and intra-peritoneal amitriptyline twice daily × 3 days. Responses to thermal and mechanical stimuli, as well as sodium channel expression in injured dorsal root ganglion (DRG) and activated glial cells in spinal dorsal horn (SDH) were measured pre-operatively and on post-operative day (POD) 4, 7, 14, 21 and 28.ResultsSNL-evoked hyper-sensitivity responses to thermal and mechanical stimuli, up-regulated Nav1.3 and down-regulated Nav1.8 expression in DRG, and activated microglia and astrocytes in SDH. In group A, intra-peritoneal amitriptyline alone alleviated thermal hypersensitivity on POD7, reversed Nav1.8 and reduced activated microglia on POD14. In group P, intrathecal pretreatment with amitriptyline not only potentiated the effect of intra-peritoneal amitriptyline on thermal hypersensitivity and Nav1.8, but attenuated mechanical hypersensitivity on POD7 and reduced up-regulated Nav1.3 on POD14. Furthermore, this treatment regimen reduced astrocyte activation on POD14.ConclusionsConcomitant intrathecal pretreatment and post-injury intra-peritoneal amitriptyline was more effective than post-injury treatment alone on attenuation of behavioral hypersensitivity, decrease of activated microglia and astrocytes and dysregulated Nav1.3 and 1.8.

Preventive and Alleviative Effect of Tramadol on Neuropathic Pain in Rats: Roles of α2-Adrenoceptors and Spinal Astrocytes

“…Consistent with our findings, Cheng et al recently reported that a combination of intrathecal pretreatment and post-injury intraperitoneal amitriptyline suppressed peripheral nerve injury-induced mechanical allodynia and activation of spinal astrocytes, although it suppressed also the activation of spinal microglia (57). Several reports indicate that TCAs can directly act on astrocytes.…”

Full-length membrane-bound tumor necrosis factor-α acts through tumor necrosis factor receptor 2 to modify phenotype of sensory neurons

“…Both spontaneous pain and peripheral sensitization reflect reduced thresholds for activation of peripheral sensory nerves, an effect that is caused in part by alterations in voltage gated channels that are the critical determinants of neuronal excitability [3; 5; 14; 15; 22]. …”

“…In order to explore whether microglial expression of mTNFα might also affect the phenotype of primary afferents, in the current study we used co-culture of COS-7 cells expressing cr TNFα with primary DRG neurons in vitro to determine the effect of cr TNFα on the expression of genes whose products are implicated in the pathogenesis of chronic neuropathic pain: the cation channel isoforms Na V 1.7 Na V 1.8, Ca V 3.2 and CCL2 [3; 5; 14; 15; 22; 23]. We found that co-culture of DRG neurons with cr TNFα-expressing COS-7 cells, but not exposure of the neurons to sTNFα, resulted in an increase in the expression of the voltage gated sodium channel isoforms Na V 1.7 and Na V 1.8, and the voltage gated calcium channel isoform Ca V 3.2.…”

Topical Ambroxol 20% for the Treatment of Classical Trigeminal Neuralgia – A New Option? Initial Clinical Case Observations

“…Sodium Channel Blockers and Trigeminal Na v 1.7 and Na v 1.8 Blockade.-In TGN, the trigeminal nociceptive system is sensitized 48 and sodium channel Potentially involved 9 TTX-r currents mediated by Na v 1.9 15 Medication with sodium channel blockade Carbamazepine Recommended; blocks only a very small extent of TTX-r-channels (Na v 1.7 and 1.8) 53,82 Na v 1.7 28,80,81 and Na v 1.8 blockade 13,14 Amitriptyline Recommended; blocks Na v 1.7 [83][84][85] and Na v 1.8 84 Na v 1.7 28,80,81 and Na v 1.8 blockade 13,14 Lamotrigine Recommended; blocks only a very small extent of TTX-r-channels (Na v 1.7 and 1.8) 53,82 Na v 1.7 28,80,81 and Na v 1.8 blockade 13,14 Phenytoin…”