Effects of pregabalin on the nociceptive, emotional and cognitive manifestations of neuropathic pain in mice

Abstract

Background Preclinical drug discovery for the treatment of chronic pain is at present challenged by the difficulty to study behaviours comparable to the complex human pain experience in animals. Several reports have demonstrated a frequent association of chronic pain in humans with affective disorders, such as anxiety and depression, and impaired cognitive functions, including memory and decision making, and motivation for goal‐directed behaviours. In this study, we validated different behavioural outcomes to measure the emotional and cognitive manifestations of neuropathic pain induced in mice by partial sciatic nerve ligation. Methods In these mice, we evaluated at different time points the nociceptive responses, the anxiety‐ and depressive‐like behaviours, the anhedonic state, object recognition memory and the operant responding maintained by food and the effects of the repeated administration of pregabalin on these manifestations. Results Our results demonstrated that the presence of allodynia and hyperalgesia in neuropathic pain mice was associated with increased anxiety‐ and depressive‐like behaviours, reduced memory functions, development of an anhedonic state and impaired motivation to obtain food in the operant task. Chronic pregabalin treatment improved the nociceptive, anxiety‐like and anhedonic responses, as well as the memory deficit, but did not modify the depressive‐like alterations and the decreased motivation in these mice. Conclusions These results indicate that some emotional manifestations of chronic pain do not necessarily resolve when pain is relieved and underline the relevance to evaluate multiple behavioural responses associated with chronic pain, including the affective‐motivational and cognitive behaviours, to increase the predictive value of preclinical drug discovery. What does this study add? In this study, we have validated different behavioural outcomes allowing a reliable measurement of the emotional and cognitive manifestations of neuropathic pain induced in mice by partial sciatic nerve ligation. These results underline the relevance to evaluate these multiple pain‐related alterations to improve the predictive value of preclinical drug discovery.

Operant self‐administration of pregabalin in a mouse model of neuropathic pain

“…A partial reversal of thermal and mechanical hypersensitivity was shown after pregabalin self‐administration. This is in agreement with a number of publications assessing the antinociceptive effects of pregabalin in neuropathic pain models in rodents (Field et al., , ; Nozaki‐Taguchi et al., ; Kremer et al., ; La Porta et al., ). It has been suggested that pregabalin can activate the descending noradrenergic system to alleviate both mechanical and heat sensitivity associated with the nerve injury (Takeuchi et al., ).…”

“…Thus, knockout mice for α2δ receptors, the main site of action of pregabalin, showed increased neuropathic mechanosensitivity, whereas thermal hyperalgesia was unaffected (Patel et al., ). In addition, pregabalin did not modify mechanical and thermal thresholds in sham‐operated mice, as expected from previous studies showing unchanged nociceptive thresholds after different pregabalin treatments (Kremer et al., ; La Porta et al., ).…”

Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse

“…La Porta et al (2016) reported ipsilateral mechanical and cold allodynia from day 3 to day 27 post-partial sciatic nerve ligation (PSNL) in Swiss albino male mice, with enhanced anxiety-like behavior in the elevated plus maze from 1 to 3 weeks post-PSNL and increased depressive-like behavior during FST, but only at 3 weeks post-PSNL. Also, a significant decrease in sucrose preference was observed from day 1 to day 20 post-PSNL.…”

Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

“…The effects of genetic inactivation of MOP and DOP on neuropathic pain manifestations were evaluated using a battery of tests to assess nociception, anxiety‐like behaviour, depressive‐like behaviour and long‐term memory, as previously reported (La Porta, Lara‐Mayorga, Negrete, & Maldonado, ; Liu & Chen, ). Briefly, animals were habituated three times on alternative days to the environment of nociceptive tests.…”