Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain

Abstract

A distal symmetrical sensory peripheral neuropathy is frequently observed in people living with Human Immunodeficiency Virus Type 1 (HIV-1). This neuropathy can be associated with viral infection alone, probably involving a role for the envelope glycoprotein gp120; or a drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors as a component of highly active anti-retroviral therapy. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). Systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity (33% decrease in limb withdrawal threshold) that when combined with perineural HIV-gp120 is exacerbated (48% decrease in threshold) and both treatments result in thigmotactic (anxiety-like) behaviour. Immunohistochemical studies revealed little ddC-associated alteration in DRG phenotype, as compared with known changes following perineural HIV-gp120. However, the chemokine CCL2 is significantly expressed in the DRG of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fibre density, comparable to that seen in herpes zoster infection. Moreover, a spinal gliosis is apparent at times of peak behavioural sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone. Treatment with the microglial inhibitor, minocycline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120+ddC model and reversal of some measures of thigmotaxis. Finally, the hypersensitivity to mechanical stimuli was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. These data suggests that both neuropathic pain models display many features of HIV- and anti-retroviral-related peripheral neuropathy. They therefore merit further investigation for the elucidation of underlying mechanisms and may prove useful for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain.

Animal Models of Peripheral Neuropathies

“…This model was useful in evaluating the potential therapeutic efficacy of commonly used anti-neuropathic pain medications, such as gabapentin, morphine, and cannabinoids. The neuropathic pain behavior in this model was exacerbated when anti-retroviral drug zalcitabine was given systemically [112], mirroring the experience in the transgenic mouse model of HIV-SN. Furthermore, these animals developed reduction in intraepidermal nerve fiber density, which is consistent with true neuropathy.…”

Enhanced c‐Fos expression in the central amygdala correlates with increased thigmotaxis in rats with peripheral nerve injury

“…Having demonstrated development of hind paw mechanical hypersensitivity in SNT rats at POD 14, we used an open field arena (OF) to assess possible alterations in spontaneous exploratory activity previously observed in rodent models of traumatic nerve injury (Wallace et al., 2007b; Blackbeard et al., 2012; Huang et al., 2013). There was a significant effect of group on both duration in the inner zone ( F (24,2) = 14.25, p  < 0.001), and frequency of entry (Kruskal–Wallis chi‐squared value = 10.427, df = 2, p  = 0.0054).…”

“…No sensory changes were detected in the right/contralateral paw of SNT animals, or in either paw of naive and sham animals. Changes were not associated with a reduction in locomotion, as evidenced by constant locomotor activity, which was within the 6000–8000 cm range seen in previous studies (Morland et al., 2015; Hasnie et al., 2007; Wallace et al., 2007b; Blackbeard et al., 2012). Previous studies have shown that hind paw mechanical withdrawal thresholds (PWT) are reduced following L5 and L5/L6 SNT, with hypersensitivity evident from 2 to 4 days (Lee and Kim, 2007; Blackbeard et al., 2012) to 10 weeks, returning to baseline by 14 weeks post‐surgery (Leinders et al., 2013).…”

“…Other studies from this group found inner zone duration was reduced 7 days after SNT, and noted reduced distance travelled, indicative of motor impairment when compared to naive animals (Blackbeard et al., 2012), with a later study on PSNI also demonstrating an association with increased thigmotactic behaviour in rats compared to sham animals (Wallace et al., 2007c). Thigmotactic deficits are sensitive to pharmacological intervention, as demonstrated by studies showing gabapentin increases inner zone activity to naive levels in SNT (Hasnie et al., 2007), and also in ddC‐treated animals (Wallace et al., 2008; Smith et al., 2014), with similar effects seen in morphine or diazepam treatment of ddC‐induced neuropathy (Wallace et al., 2008), whereas the microglial inhibitor, minocycline, only ameliorates thigmotactic deficits in animals treated with ddC combined with GP‐120 HIV viral protein (Wallace et al., 2007b). Previous data on open field locomotor effects suggest that both traumatic and inflammatory (Morland et al., 2015) pain models are associated with decreased locomotor activity at the time points tested, whereas systemic induction methods such as viral and drug‐induced models are not.…”

“…Behavioural alterations have been described in rat models of peripheral traumatic nerve injury (Hu et al., 2007; Blackbeard et al., 2012; Galan‐Arriero et al., 2015; Wang et al., 2015; Avila‐Martin et al., 2015; Grégoire et al., 2012), neuropathic viral infection (Hasnie et al., 2007; Wallace et al., 2007a) and drug‐induced neuropathies (Wallace et al., 2007b; Huang et al., 2013). …”