Background & Aims
Neuropathic pain is a form of maladaptive plasticity[1] associated with neurobiological adaptation in brain reward pathways[2]. Pain relief produces negative reinforcement through activation of the mesolimbic reward circuit[3]. Pathological pain may produce negative affective states, anhedonia and motivational states that facilitate drug-seeking and/or pain relief[4]. However, pain relief may also become less rewarding (i.e., reward-deficiency) and more aversive (i.e., anti-reward) over time. Pain-induced transformations in reward processing enhances motivational salience to pain, analgesia and related cues[4], affecting sensitivity to opioids and non-opioid analgesics[2]. We previously reported that rats with spared nerve injury exhibited increases in morphine-seeking behavior during extinction[5]. Here, we tested the hypothesis that mice subjected to traumatic nerve injury sparing the tibial nerve (SNIt) would produce negative affective states that impact opioid addictive behaviors.
Methods
We used a mouse model of traumatic neuropathic nerve injury where the tibial branch of the sciatic nerve is spared, and the peroneal and sural branches are ligated and cut (SNIt). This model produces a robust mechanical hypersensitivity in the von Frey test while leaving sensitivity to heat intact and does not produce motor impairment[6]. By employing i.v. self-administration in mice, we studied the effects of SNIt in morphine self-administration, relapse-like behavior, and motivation to work for morphine infusions. We also examined whether SNIt would affect oral oxycodone consumption and seeking in a two-bottle choice (TBC) paradigm. We also studied how SNIt influences food self-administration and the motivation to work for food rewards. Affective states were measured using the light/dark box, elevated plus maze, open field, marble burying, sucrose preference, nest building, chocolate preference, and forced swim test. Comparisons were made with sham-operated and naive groups.
Results
SNIt, sham-operated and naive groups exhibited similar levels of i.v. morphine intake on fixed ratio 1 (FR1), FR2 and FR3 schedules. Likewise, no differences were found in the motivation to work for morphine infusions. All groups displayed similar motivation to work for natural rewards in the food self-administration task. Overall, SNIt mice tended to consume less oxycodone than the other groups in the TBC paradigm, whereas no distinctions were detected between groups in the oxycodone-seeking test after forced abstinence. Strikingly, no differences were observed between SNIt, sham-operated and naive groups in affective states measured in the light/dark box, elevated plus maze, open field, marble burying, sucrose preference, nest building, chocolate preference, or forced swim test. Robust mechanical allodynia was observed in SNIt but not sham-operated or naive groups throughout the observation interval.
Conclusions
Our results suggest that traumatic neuropathic nerve injury in the SNIt model did not reliably increase negative affective states or opioid vulnerability in male mice. Lower oxycodone consumption in the SNIt group could indicate that pain relief is becoming less rewarding and more aversive overall. Further studies are necessary to document the effects of traumatic neuropathic nerve injury in female mice and susceptibility to opioid addiction. Our studies provide insight into abuse liability of narcotic analgesics in pathological pain states.
References
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Presenting Author
Idaira Oliva
Poster Authors
Topics
- Models: Chronic Pain - Neuropathic