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. 2011 Mar;114(3):624-32.
doi: 10.1097/ALN.0b013e31820a4edb.

Opioid facilitation of rewarding electrical brain stimulation is suppressed in rats with neuropathic pain

Eric E Ewan  1 , Thomas J Martin
Affiliations

Opioid facilitation of rewarding electrical brain stimulation is suppressed in rats with neuropathic pain

Eric E Ewan et al. Anesthesiology. 2011 Mar.

Abstract

Introduction: Opioids are powerful analgesics, but are also common drugs of abuse. Few studies have examined how neuropathic pain alters the pharmacology of opioids in modulating limbic pathways that underlie abuse liability.

Methods: Rats with or without spinal nerve ligation (SNL) were implanted with electrodes into the left ventral tegmental area and trained to lever press for electrical stimulation. The effects of morphine, heroin, and cocaine on facilitating electrical stimulation of the ventral tegmental area and mechanical allodynia were assessed in SNL and control subjects.

Results: Responding for electrical stimulation of the ventral tegmental area was similar in control and SNL rats. The frequency at which rats emitted 50% of maximal responding was 98.2 ± 5.1 (mean ± SEM) and 93.7 ± 2.8 Hz in control and SNL rats, respectively. Morphine reduced the frequency at which rats emitted 50% of maximal responding in control (maximal shift of 14.8 ± 3.1 Hz), but not SNL (2.3 ± 2.2 Hz) rats. Heroin was less potent in SNL rats, whereas cocaine produced similar shifts in control (42.3 ± 2.0 Hz) and SNL (37.5 ± 4.2 Hz) rats.

Conclusions: Nerve injury suppressed potentiation of electrical stimulation of the ventral tegmental area by opioids, suggesting that the positive reinforcing effects are diminished by chronic pain. Given concerns regarding prescription opioid abuse, developing strategies that assess both analgesia and abuse liability within the context of chronic pain may aid in determining which opioids are most suitable for treating chronic pain when abuse is a concern.

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Figures

Figure 1
Figure 1. Schematic showing the location of stimulating electrodes within the ventral tegmental area for control and spinal nerve-ligated (SNL) rats
Numbers next to diagrams indicate the distance anterior to the interaural line according to the atlas of Paxinos and Watson.
Figure 2
Figure 2. Development of mechanical allodynia following spinal nerve ligation (SNL) and baseline responding for electrical stimulation of the ventral tegmental area in control and SNL rats
(A) Paw withdrawal thresholds (PWT) were assessed between 14–21 days after surgery using von Frey filaments in control and SNL rats. (B) Frequency-response curves for baseline responding were generated by averaging the third and fourth components preceding saline administration (prior to any drug treatments). The y-axis indicates the number of self-stimulations (0.5-sec) during each 50-sec trial for each frequency (x-axis). Data shown are averages across control (n=11) and SNL (n=11) rats. Average current intensities during baseline responding were 139.6 (14.23) uA for control and 138.6 (9.83) uA for SNL rats. # Significantly different from control rats P ≤ 0.05.
Figure 3
Figure 3. Effects of spinal nerve ligation (SNL) on morphine facilitation of electrical stimulation of the ventral tegmental area for drug incubation times of 15-min (A) and 60-min (B)
Reduction in EF50 (frequency at which rats emitted 50% of maximal responding) was calculated by subtracting the EF50 for the three components following drug injection (5–7) from the EF50 for the two components preceding drug injection (3–4) for each dose assessed. Data shown are averages across control (n=7–8) and SNL (n=6–7) rats. Frequency-response curves before and after 3mg/kg morphine (60-min) are shown for control (C, n=8) and SNL (D, n=7) rats. * Significantly different from saline treatment P ≤ 0.05. # Significantly different from SNL rats P ≤ 0.05.
Figure 4
Figure 4. Effects of spinal nerve ligation (SNL) on heroin facilitation of electrical stimulation of the ventral tegmental area
(A) Reduction in EF50 (frequency at which rats emitted 50% of maximal responding) was calculated by subtracting the EF50 for the three components following drug injection (5–7) from the EF50 for the two components preceding drug injection (3–4) for each dose assessed. Data shown are averages across control (n=6–7) and SNL (n=7–8) rats. Frequency-response curves before and after 0.1 mg/kg heroin (15-min) are shown for control (B, n=6) and SNL (C, n=8) rats. * Significantly different from saline treatment P ≤ 0.05.
Figure 5
Figure 5. Effects of spinal nerve ligation (SNL) on cocaine facilitation of electrical stimulation of the ventral tegmental area
(A) Reduction in EF50 (frequency at which rats emitted 50% of maximal responding) was calculated by subtracting the EF50 for the three components following drug injection (5–7) from the EF50 for the two components preceding drug injection (3–4) for each dose assessed. Data shown are averages across control (n=6–7) and SNL (n=7–8) rats. Frequency-response curves before and after 10 mg/kg heroin (15-min) are shown for control (B, n=7) and SNL (C, n=8) rats. * Significantly different from saline treatment P ≤ 0.05.
Figure 6
Figure 6. Drug effects on paw withdrawal thresholds (PWT) in spinal nerve-ligated (SNL) rats
Dose-effect curves were determined for morphine (A), heroin (B), and cocaine (C) on PWT in SNL rats at the indicated times following an intraperitoneal injection (n=6). * Significantly different from saline treatment P ≤ 0.05.
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