A partial L5 spinal nerve ligation induces a limited prolongation of mechanical allodynia in rats: an efficient model for studying mechanisms of neuropathic pain

Abstract

The relationship between pain severity and the extent of injury to a peripheral nerve remains elusive. In this study, we compared the pain behavior resulting from partial (1/3-1/2 thickness) and full L5 spinal nerve ligation (SNL) in rats. The decrease in paw withdrawal threshold (PWT) to mechanical stimuli in the hindpaw ipsilateral to the injury was comparable in the two groups on days 3-21 post-injury. However, the decreased PWT recovered earlier in the partial SNL group than in the full SNL group. These observations suggest that the duration of neuropathic pain behavior, but not the early development of mechanical allodynia, is dependent on the extent of nerve injury. On days 6 and 15 post-injury, when the mechanical allodynia was similar in the two groups, systemic morphine induced a greater reduction of mechanical allodynia in the partial SNL group than in the full SNL group. Furthermore, in partial SNL rats, at post-injury time points when they had largely recovered from the neuropathic pain state, systemic administration of naloxone hydrochloride (day 53) or naloxone methiodide (a non-selective peripherally acting opioid receptor antagonist; day 64) or intra-plantar injection of naloxone methiodide rekindled mechanical pain hypersensitivity in the ipsilateral hindpaw, suggesting a prolonged activation of endogenous opioidergic pain-inhibition. Therefore, partial SNL in rats may represent an efficient model for studying the mechanisms of neuropathic pain, testing effects of analgesic/antihyperalgesic drugs, and understanding endogenous pain-inhibitory mechanisms that lead to reversal of the pain behavior with time.

Fig. 1

Rats showed less persistent mechanical allodynia and increased sensitivity to morphine analgesia after a partial L5 spinal nerve ligation (SNL) than after a full SNL. (A) A full L5 SNL (n=11) induced a remarkable decrease in PWT in the hindpaw ipsilateral to the injury that lasted for more than 70 days, whereas a partial L5 SNL (n=17) induced mechanical allodynia that lasted only to day 42 post-injury. The PWTs were significantly higher in the partial SNL group than in the full SNL group from day 25 to day 70 post-injury. (B) There were no significant changes in PWT of the contralateral hindpaw in either group after injury. (C-D) Morphine sulfate (1.5 mg/kg, s.c.) significantly increased the PWT of the ipsilateral hindpaw in both partial SNL (n=10) and full SNL (n=6) groups at 30 min post-injection on day 6 (C) and day 15 (D) post-injury. Although the PWTs were comparable between the two groups before morphine injection, the PWT at 30 min post-morphine injection was significantly higher in the partial SNL group than in the full SNL group. # P< 0.05 versus the pre-drug baseline. * P < 0.05 versus the full SNL group. Data are presented as means ± SEM.

Fig. 2

Blocking systemic and peripheral opioid receptors rekindled mechanical pain hypersensitivity in the partial SNL rats after they had recovered from the neuropathic pain state. (A) On day 53 post-injury, the PWT in the partial SNL group (n=7) was significantly higher than that in the full SNL group (n=6). The intraperitoneal injection of naloxone hydrochloride (10 mg/kg, i.p.) significantly decreased the PWT in the partial SNL group but not in the full SNL group. (B) On day 64 post-injury, systemic administration (i.p.) of naloxone methiodide (MB-Naloxone; 5 mg/kg) also significantly reduced PWT at 30 min post-injection in the partial SNL group. Six hours later, when the PWT had returned to near pre-drug level, an intra-plantar (i.pl.) injection of naloxone methiodide (50 μg/50 μl) again invoked mechanical pain hypersensitivity in the partial SNL rats. There were no significant changes in PWT of the contralateral hindpaw after drug treatments. # P < 0.05 versus the pre-drug baseline. * P < 0.05 versus the full SNL group. Data are presented as means ± SEM.