Pharmacological characterisation of the tibial nerve transection (TNT) model of neuropathic pain using a fully blind experimental protocol

Denise Richardson, Janet Nicholson, Ian Machin, Rachel Combe

Pfizer, Sandwich, Kent, UK, UK

The tibial nerve transection (TNT) model of neuropathic pain is a peripheral nerve injury model, involving injury to a distal branch of the sciatic nerve, which leads to a more consistent and sustained mechanical and cold allodynia compared to ligation models of neuropathic pain (Lee et al., 2000; Hofmann et al., 2003). However, there is a relative lack of pharmacological characterisation of this model compared to other, more commonly used models of neuropathic pain.

The aim of the present study was to measure the effect of several clinically used compounds on established mechanical allodynia present in TNT-operated rats, using a fully blind protocol.

TNT surgery was performed on anaesthetised male Sprague-Dawley rats (200-250 g, CRUK) (Lee et al., 2000). From 14 days post-surgery the effects of gabapentin (30, 60 or 100 mg/kg, p.o.), pregabalin (10 or 20 mg/kg, p.o.), oxycodone (0.3 mg/kg, s.c.) or their respective vehicles (water, water or saline, 1ml/kg) on mechanical allodynia in TNT rats was tested up to 3 hours post-dose. For the fully blind protocol one colleague randomised animals to treatment groups and carried out the dosing, whilst the experimenter remained blind to treatment and grouping. Doses were chosen to, where possible, avoid sedative side effects of these compounds, to maintain the blinding of the studies. Behaviour was measured using a modified version of the Dixon up-down von Frey method to produce 50% paw withdrawal threshold (PWT) values (Chaplan et al., 1994).

Figure 1

Mechanical allodynia present in tibial nerve transected (TNT) rats can be significantly reversed by both gabapentin (100 mg/kg) and pregabalin (10 and 20 mg/kg) when compared to vehicle-treated rats. Oxycodone produces no effect on mechanical allodynia. Data are expressed as mean + SEM (n = 7-16 rats per group) * P < 0.05, ** P < 0.01 vs vehicle equivalent.

Reversal of established mechanical allodynia using gabapentin and pregabalin showed that a dose-response relationship can be observed using a fully blind protocol in this model of neuropathic pain. Oxycodone was, however, unable to reverse TNT-induced mechanical allodynia, at a dose and time shown to be effective in another model of chronic pain (monoiodoacetate model, data not shown). Overall, we have confirmed that TNT rats display robust and sustained allodynia which can be reversed by the clinically used analgesics gabapentin and pregabalin.

Chaplan S.R. et al., (1994) J Neurosci Methods, 53(1): 55-63.

Hofmann H.A. et al., (2003) Eur J Pharmacol. 470(1-2): 17-25.

Lee B.H. et al., (2000) Neuroreport 11(4): 657-61.