Effect of Gabapentin in a Neuropathic Pain Model in Mice Overexpressing Human Wild-Type or Human Mutated Torsin A

Abstract

Background: DYT1 dystonia is the most common form of early-onset inherited dystonia, which is caused by mutation of torsin A (TA) belonging to the “ATPases associated with a variety of cellular activities” (AAA + ATPase). Dystonia is often accompanied by pain, and neuropathic pain can be associated to peripherally induced movement disorder and dystonia. However, no evidence exists on the effect of gabapentin in mice subjected to neuropathic pain model overexpressing human normal or mutated TA. Methods: Mice subjected to L5 spinal nerve ligation (SNL) develop mechanical allodynia and upregulation of the α2δ-1 L-type calcium channel subunit, forming a validated experimental model of neuropathic pain. Under these experimental conditions, TA is expressed in dorsal horn neurons and astrocytes and colocalizes with α2δ-1. Similar to this subunit, TA is overexpressed in dorsal horn 7 days after SNL. This model has been used to investigate (1) basal mechanical sensitivity; (2) neuropathic pain phases; and (3) the effect of gabapentin, an α2δ-1 ligand used against neuropathic pain, in non-transgenic (NT) C57BL/6 mice and in mice overexpressing human wild-type (hWT) or mutant (hMT) TA. Results: In comparison to non-transgenic mice, the threshold for mechanical sensitivity in hWT or hMT does not differ (Kruskal–Wallis test = 1.478; p = 0.4777, although, in the latter animals, neuropathic pain recovery phase is delayed. Interestingly, gabapentin (100 mg/Kg) reduces allodynia at its peak (occurring between post-operative day 7 and day 10) but not in the phase of recovery. Conclusions: These data lend support to the investigation on the role of TA in the molecular machinery engaged during neuropathic pain.

Exploitation of Thermal Sensitivity and Hyperalgesia in a Mouse Model of Dystonia

“…However, a trend toward an increased hyperalgesia is present in hWT and hMT mice compared to NT mice, but it does not reach statistical significance. Previous results from our research group have demonstrated that there are no significant differences in baseline mechanical sensitivity among the three strains [ 35 ]. Moreover, the transgenic mice have shown prolonged mechanical allodynia after SNL, suggestive of delayed recovery [ 35 ].…”

“…Previous results from our research group have demonstrated that there are no significant differences in baseline mechanical sensitivity among the three strains [ 35 ]. Moreover, the transgenic mice have shown prolonged mechanical allodynia after SNL, suggestive of delayed recovery [ 35 ]. Nevertheless, the effect of the human gene on pain processing cannot be excluded [ 35 ].…”

“…Moreover, the transgenic mice have shown prolonged mechanical allodynia after SNL, suggestive of delayed recovery [ 35 ]. Nevertheless, the effect of the human gene on pain processing cannot be excluded [ 35 ]. This difference between thermal sensitivity and hyperalgesia and mechanical sensitivity can be due to the diverse sensory information processing and development of mechanical allodynia and thermal hyperalgesia to heat.…”

“…These channels can be involved both in peripheral and in central sensitization, as shown also in aged C57BL/6 mice in formalin test [ 42 ]. Torsin A colocalizes with α2δ-1 L-type voltage-dependent calcium channel subunit upregulated during neuropathic pain, in the γ-aminobutyric acid (GABA)-ergic and glutamatergic neurons of the dorsal horn superficial laminae [ 35 ] that regulate pain processing to central areas. In particular, torsin A has been associated with disinhibition of striatal GABAergic synaptic activity [ 43 ] and GABA-ergic inhibition after nerve injury is necessary to avoid the development of aberrant processing of sensory information within the dorsal horn [ 44 ].…”

“…116/1992). The sample power was calculated by routine formula and setting power to 80% and α = 0.05, according to similar studies in the literature [ 35 ] to obtain reliable results while keeping the number of animals as low as possible, based on the 3R approach to refine, reduce, and, at least in part, replace. The experimental procedures were approved by Fondazione Santa Lucia and University Tor Vergata Animal Care and Use Committees, and the Italian Ministry of Health.…”