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Differential Suppression of Intracranial Self-Stimulation, Food-Maintained Operant Responding, and Open Field Activity by Paw Incision and Spinal Nerve Ligation in Rats

Ewan, Eric E. PhD*; Martin, Thomas J. PhD

doi: 10.1213/ANE.0000000000000119
Pain and Analgesic Mechanisms: Research Report

BACKGROUND: Detection of ongoing spontaneous pain behaviors in laboratory animals remains a research challenge. Most preclinical pain studies measure elicited behavioral responses to an external noxious stimulus; however, ongoing spontaneous pain in humans and animals may be unrelated to hypersensitivity, and likely diminishes many behaviors, particularly motivated behaviors, that we hypothesize will decrease after induction of acute and chronic pain.

METHODS: In this study, 201 male rats were subjected to paw incision (INC), L5/L6 spinal nerve ligation (SNL), or INC in SNL rats, and the effects on paw withdrawal threshold (PWT) were assessed. For comparison, the behavioral-decreasing effects on nonevoked measures, including lever pressing for rewarding electrical stimulation of the ventral tegmental area intracranial self-stimulation (VTA ICSS) or food reinforcement (FR), and open field activity (OFA), were also assessed in these same rats.

RESULTS: INC decreased PWT for 4 days, decreased VTA ICSS for 2 days, and FR for 1 day but did not alter OFA. SNL decreased PWT similarly to INC but did not decrease VTA ICSS or FR; SNL did however decrease OFA. INC in SNL rats reduced PWT, VTA ICSS, and FR similarly to INC alone and did not decrease OFA compared with SNL alone.

CONCLUSIONS: The acute effects of INC on decreasing lever pressing for VTA ICSS and FR (1–2 days after incision) correspond to the timeframe in which ongoing spontaneous pain is expected to occur after INC. Therefore, these decreases are likely mediated by ongoing spontaneous pain, which may be unrelated to mechanical hypersensitivity that persists for up to 4 days after INC. PWT is decreased similarly by SNL, yet operant behavior (lever pressing for VTA ICSS and FR) was not decreased by SNL. SNL, but not INC, decreased rearing behavior but not total distance traveled during OFA. This further indicates that the presence and the extent of hypersensitivity are not predictive of many behavioral changes in rats thought to be mediated by the presence of ongoing pain. Surprisingly, the behavioral effects of INC are not exacerbated in SNL rats. These data support the growing belief that acute pain models produce short-lived spontaneous pain behaviors that are often less pronounced or absent in neuropathic pain models, and highlight the need for assessment of both evoked and nonevoked pain behaviors in developing future therapies for acute and chronic pain.

From the *Department of Neurological Surgery, University of Louisville, Louisville, Kentucky; and Department of Anesthesiology, Wake Forest University Health Sciences, Winston-Salem, North Carolina.

Accepted for publication December 18, 2013.

Funding: Supported by DA-0022599 (TJM) and T32-DA-007246 (EEE) from the National Institute on Drug Abuse of the National Institutes of Health, Bethesda, MD.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Eric E. Ewan, PhD, Department of Neurological Surgery, University of Louisville, 511 South Floyd St., Room 609, Louisville, KY, 40292. Address e-mail to

© 2014 International Anesthesia Research Society