Systemic administration of propentofylline, ibudilast, and (+)-naltrexone each reverses mechanical allodynia in a novel rat model of central neuropathic pain

Abstract

Central neuropathic pain (CNP) is a debilitating consequence of central nervous system damage for which current treatments are ineffective. To explore mechanisms underlying CNP, we developed a rat model involving T13/L1 dorsal root avulsion. The resultant dorsal horn damage creates bilateral below-level (L4-L6) mechanical allodynia. This allodynia, termed spinal neuropathic avulsion pain, occurs in the absence of confounding paralysis. To characterize this model, we undertook a series of studies aimed at defining whether spinal neuropathic avulsion pain could be reversed by any of 3 putative glial activation inhibitors, each with distinct mechanisms of action. Indeed, the phosphodiesterase inhibitor propentofylline, the macrophage migration inhibitory factor inhibitor ibudilast, and the toll-like receptor 4 antagonist (+)-naltrexone each reversed below-level allodynia bilaterally. Strikingly, none of these impacted spinal neuropathic avulsion pain upon first administration but required 1 to 2 weeks of daily administration before pain reversal was obtained. Given reversal of CNP by each of these glial modulatory agents, these results suggest that glia contribute to the maintenance of such pain and enduring release of macrophage migration inhibitory factor and endogenous agonists of toll-like receptor 4 is important for sustaining CNP. The markedly delayed efficacy of all 3 glial modulatory drugs may prove instructive for interpretation of apparent drug failures after shorter dosing regimens.

Perspective: CNP that develops after trauma is often described by patients as severe and intolerable. Unfortunately, current treatments are not effective. This work suggests that using pharmacologic treatments that target glial cells could be an effective clinical treatment for CNP.

Keywords: Avulsion; d-naltrexone; glia; pain; toll-like receptor 4.

Copyright © 2014 American Pain Society. All rights reserved.

Figures

Figure 1

Assessment of the effects of propentofylline (PPF) on SNAP. Rats were tested for mechanical allodynia across a timecourse on both the ipsilateral (A) and contralateral (B) hindpaw. Rats that received PPF (10 mg/kg, i.p.) for 35 days beginning 28 days after surgery were significantly less allodynic than rats that received vehicle in both the ipsilateral (C) and contralateral (D) hindpaw. Data are presented as mean ± SEM and analyzed using a two-way ANOVA on the AUCs, n=6–8/group. *p<0.05 compared to all other groups.

Figure 2

Detailed timecourse of the effects of PPF on SNAP. Rats were tested for mechanical allodynia across a timecourse on both the ipsilateral (A) and contralateral (B) hindpaw. Rats that received PPF (10 mg/kg, i.p.) for 14 days beginning 28 days after surgery were significantly less allodynic than rats that received vehicle in both the ipsilateral (C) and contralateral (D) hindpaw. Data are presented as mean ± SEM and analyzed using a two-way ANOVA on the AUCs, n=6 per group. *p<0.05 compared to all other groups

Figure 3

Assessment of the effects of ibudilast administered late in the development of SNAP. Rats were tested for mechanical allodynia across a timecourse on both the ipsilateral (A) and contralateral (B) hindpaw. Rats that received ibudilast (10 mg/kg, s.c.) for 35 days beginning 28 days after surgery were significantly less allodynic than rats that received vehicle in both the ipsilateral (C) and contralateral (D) hindpaw. Data are presented as mean ± SEM and analyzed using a two-way ANOVA on the AUCs, n=6–8 per group. *p<0.05 compared to all other groups.

Figure 4

Assessment of the effects of ibudilast administered early in the development of SNAP. Rats were tested for mechanical allodynia across a timecourse on both the ipsilateral (A) and contralateral (B) hindpaw. Rats that received ibudilast (10 mg/kg, s.c.) for 21 days beginning 14 days after surgery were significantly less allodynic than rats that received vehicle in both the ipsilateral (C) and contralateral (D) hindpaw. Data are presented as mean ± SEM and analyzed using a two-way ANOVA on the AUCs, n=5–6 per group. *p<0.05 compared to all other groups, +p<0.05 compared to Sham+Vehicle and Sham+Ibudilast.

Figure 5

Assessment of the effects of (+)-naltrexone on SNAP. Rats were tested for mechanical allodynia across a timecourse on both the ipsilateral (A) and contralateral (B) hindpaw. Rats that received (+)-naltrexone (6 mg/kg, s.c.) for 14 days beginning 32 days after surgery were significantly less allodynic than rats that received vehicle in both the ipsilateral (C) and contralateral (D) hindpaw. Data are presented as mean ± SEM and analyzed using a one-way ANOVA on the AUCs, n=6 per group. *p<0.05 compared to all other groups.

Figure 6

Assessment of the effects of ceasing (+)-naltrexone on SNAP. Rats were tested for mechanical allodynia across a timecourse on both the ipsilateral (A) and contralateral (B) hindpaw. Rats that received (+)-naltrexone (6 mg/kg, s.c.) for 6 days beginning 28 days after surgery were significantly less allodynic than rats that received vehicle in both the ipsilateral (C) and contralateral (D) hindpaw. After stopping (+)-naltrexone administration on day 33, rats that were receiving (+)-naltrexone returned to pre-drug allodynia thresholds in both the ipsilateral (E) and contralateral (F) hindpaw. Data are presented as mean ± SEM and analyzed using a t-test on the AUCs, n=6 per group. *p<0.05 compared to all other groups.