Pharmacological characteristics of the hind paw weight bearing difference induced by chronic constriction injury of the sciatic nerve in rats

Abstract

Aims

We examined the possible involvement of spontaneous on-going pain in the rat chronic constriction injury (CCI) model of neuropathic pain.

Main methods

The development of weight bearing deficit, as an index of spontaneous on-going pain, was investigated in comparison to that of mechanical allodynia in CCI rats. We also examined the effects of morphine and a gabapentin analogue (1S, 3R)-3-methyl-gabapentin (3-M-gabapentin) on both the CCI-induced weight bearing deficit and mechanical allodynia.

Key findings

Rats with CCI demonstrated a significant reduction in weight bearing of the injured limb with a peak at a week post-operation, which was followed by a gradual recovery for over 7 weeks. The time course of development and recovery of CCI-induced weight bearing deficit appeared to follow that of foot deformation of the affected hind limb. CCI also evoked mechanical allodynia that was fully developed on a week post-operation, but showed no recovery for at least 8 weeks. 3-M-gabapentin significantly inhibited CCI-induced mechanical allodynia, but not weight bearing deficit, at 100 mg/kg p.o. Likewise, morphine was without significant effect on CCI-induced weight bearing deficit at the dose (3 mg/kg, s.c.) that could almost completely inhibit mechanical allodynia, whereas it inhibited both mechanical allodynia and weight bearing deficit at 6 mg/kg, s.c.

Significance

The present findings suggest that CCI-induced weight bearing deficit is not a consequence of mechanical allodynia, but is attributable to spontaneous on-going pain. The rat CCI model of neuropathic pain thus represents both spontaneous on-going pain and mechanical allodynia.

Introduction

Peripheral nerve injury associated with chronic neuropathic disorders, including diabetic neuropathy and post-herpetic neuralgia, causes a characteristic pain state, designated neuropathic pain (NeP), that is manifested as a combination of spontaneous on-going pain and exaggerated sensory response to noxious and non-noxious stimuli, referred to as hyperalgesia and allodynia, respectively (Chaplan et al., 1994, Price et al., 1992). To date, several rat models have been developed for investigation of the pathogenesis and therapy of NeP (Bennett and Xie, 1988, Decosterd and Woolf, 2000, Kim and Chung, 1992, Seltzer et al., 1990). In these models, NeP is produced by spinal or sciatic nerve injury, and measured by mechanical allodynia as assessed by a characteristic behavioral sign, i.e., paw withdrawal in response to non-noxious stimulation (Bennett and Xie, 1988, Decosterd and Woolf, 2000, Kim and Chung, 1992, Seltzer et al., 1990). Since multiple methods have been established for quantitative measurement of a paw withdrawal response to non-noxious stimulation in rats (Bell-Krotoski and Tomancik 1987), mechanical allodynia has been widely investigated preclinically to assess analgesic efficacy of novel agents (Dixon, 1980, Kauppila et al., 1998, Kim and Chung, 1997, Ren, 1999, Sato et al., 1999). Few studies, however, have investigated the possible involvement of non-allodynic components such as spontaneous on-going pain and hyperalgesia in rat models of NeP.

Recently, weight bearing deficit of the limb has been proposed as an objective endpoint that can reflect spontaneous on-going pain. Other endpoints indicative of spontaneous pain include weight loss, gait abnormalities, sleep disturbance, decreased movement and spontaneous paw guarding in experimental animals (Hord et al., 2003, Imamura and Bennett, 1995, Min et al., 2001). While effects of NeP on spontaneous pain as monitored by weight baring deficit have not been investigated, a decrease in standing weight bearing of the injured limb has been observed in various types of rat pain models, including bone cancer pain, incisional pain, inflammatory pain and osteoarthritis (Bove et al., 2003, Clayton et al., 2002, Combe et al., 2004, Medhurst et al., 2002, Whiteside et al., 2003).

The purpose of the present study is to examine whether spontaneous on-going pain is involved in a rat model of neuropathic pain produced by chronic constriction injury (CCI) of the sciatic nerve. To achieve this goal, we investigated the development of weight bearing deficit in comparison to that of mechanical allodynia in rats with CCI. In addition, we examined how the CCI-induced weight bearing deficit and mechanical allodynia responded to two different classes of analgesic agents, i.e., morphine and (1S, 3R)-3-methyl-gabapentin (3-M-gabapentin), a potent ligand to α2δ subunit of voltage gated calcium channels (Bryans et al. 1998).