Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry

Abstract

Relief of pain is rewarding. Using a model of experimental postsurgical pain we show that blockade of afferent input from the injury with local anesthetic elicits conditioned place preference, activates ventral tegmental dopaminergic cells, and increases dopamine release in the nucleus accumbens. Importantly, place preference is associated with increased activity in midbrain dopaminergic neurons and blocked by dopamine antagonists injected into the nucleus accumbens. The data directly support the hypothesis that relief of pain produces negative reinforcement through activation of the mesolimbic reward-valuation circuitry.

Fig. 1.

PNB in rats with incisional pain produced VTA- and NAc-dependent CPP. PNB in injured rats 24 h, but not 96 h, following incision of the hind paw induced CPP as demonstrated by (A) increased time spent in chambers paired with popliteal fossa (PF) lidocaine and (B) difference scores. (C) Pretreatment with lidocaine or baclofen, but not naloxone, in the VTA 10 min before PNB abolished CPP. (D) Pretreatment with NAc lidocaine or flupenthixol blocked CPP. Mean ± SEM, n = 9–13, *P < 0.05, Student’s paired t test.

Fig. 2.

PNB increased the number of FOS-positive dopaminergic neurons in the VTA. (A) A coronal brain section at bregma −5.8 mm outlining the VTA identified by tyrosine hydroxylase labeling (red). (B) The average number of FOS+ cells (green) per section was calculated between bregma −5.2 and −6.8 mm. (C) The number of FOS+ cells increased significantly at bregma −5.8 to −6.3 mm only in incised rats following PNB. (D) Confocal images within the medial VTA (rectangle in Fig. 2A). The number of dopaminergic FOS+/TH+ cells (E) increased in incised rats after PNB (F); the number of nondopaminergic FOS+/TH- cells (G) did not change (H). Mean ± SEM, n = 4–5 rats/group, *P < 0.05; two-way ANOVA with Bonferroni multiple comparisons test (B), one-way ANOVA with Tukey’s multiple comparisons test (C and F).

Fig. 3.

PNB increased the extracellular dopamine (DA) levels in the NAc shell of rats with incisional pain. (A) Extracellular dopamine levels increased above basal levels following PNB only in incised animals. (B) Area under the curve (AUC) of percent change from baseline demonstrated significant dopamine release within 120 min after PNB given 24 h, but not 96 h, following incision. Mean ± SEM, n = 3–8 rats/group, *P < 0.05; one-way ANOVA with Tukey’s multiple comparisons test.