Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain

Abstract

Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1 h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analysed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH in IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain.1

Analysis of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa

“…Interestingly, the amount of depression of HVA I Ca we see with chronic application of 10 M PGB in medium and IB 4 Ϫ DRG neurons is comparable with the 40% depression seen with acute application of 100 M GBP or 10 M PGB to undefined types of cultured DRG neuron (McClelland et al 2004;Sutton et al 2002). This may imply that the rapidly developing actions of gabapentinoids seen in animal models in vivo (Kumar et al 2013) relate more to acute peripheral actions of the drug (Carlton and Zhou 1998), rather than spinal actions that take days to develop.…”

“…In confirmation of the results of Moore et al (2002), we found that gabapentinoids had little or no effect in spinal cord when applied acutely (Table 2). Despite this, gabapentinoids have been reported to act within 30 min or less in animal models of neuropathic pain in vivo (Coderre et al 2005;Kayser and Christensen 2000;Kumar et al 2013;Patel et al 2013). The reasons for this discrepancy remain to be elucidated.…”

Etiology and Pharmacology of Neuropathic Pain

“…In animal models of neuropathic pain, gabapentinoids consistently produce an antiallodynic effect within 30 minutes of administration (Hunter et al, 1997;Field et al, 2006;Narita et al, 2012;Kumar et al, 2013;Alles and Smith, 2016;Alles et al, 2017). We contend this rapidity reflects gabapentin interaction with upregulated a2d-1 and increased trafficking of VGCC from endosomes to the plasma membrane within the confine of the nerve terminal ( Fig.…”

“…Despite their rapid efficacy in animal models of neuropathic pain (Hunter et al, 1997;Field et al, 2006;Narita et al, 2012;Kumar et al, 2013;Alles and Smith, 2016;Alles et al, 2017), several reports indicate that GBP effects in clinical pain management take a day or more to develop (Cheshire, 2002;Stacey et al, 2008;Sharma et al, 2010;Rauck et al, 2013).…”

“…This process is interrupted by gabapentinoids within 30 minutes of i.p. injection and accounts for the rapid antiallodynic effect seen in nerve-injured animals (Hunter et al, 1997;Field et al, 2006;Narita et al, 2012;Kumar et al, 2013;Alles and Smith, 2016;Alles et al, 2017). This idea is supported by the observation that a rapidly developing effect of PGB in rats subject to spared nerve injury was not associated with reduced accumulation of a2d-1 in the superficial dorsal horn (Yang et al, 2014a).…”