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. 2011 Jun;229(2):502-6.
doi: 10.1016/j.expneurol.2011.03.021. Epub 2011 Mar 31.

Nucleus accumbens facilitates nociception

Robert W Gear  1 , Jon D Levine
Affiliations

Nucleus accumbens facilitates nociception

Robert W Gear et al. Exp Neurol. 2011 Jun.

Abstract

We have previously demonstrated an opioid link in nucleus accumbens (NAc) that mediates antinociception produced by a novel ascending pain modulation pathway. For example, noxious stimulation induces heterosegmental antinociception that is mediated by both mu- and delta-opioid receptors in NAc. However, spinal intrathecal administration of the mu-receptor agonist [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) also induces heterosegmental antinociception. The aim of the present study in the rat was to identify the intra-NAc opioid receptors that mediate the antinociceptive effects of spinally administered DAMGO and also to determine the effect of NAc efferent activity on nociception. Intra-NAc administration of either the mu-opioid receptor antagonist Cys(2),Tyr(3), Orn(5),Pen(7)amide (CTOP) or the delta-opioid receptor antagonist naltrindole blocked the antinociceptive effect of spinally administered DAMGO on the jaw-opening reflex (JOR). Injection of quaternary lidocaine (QX-314) attenuated the JOR, suggesting that the output of NAc is pronociceptive. In support of this, intra-NAc injection of the excitatory amino acid agonist kainate enhanced the JOR. Thus, it is possible to modulate activity in NAc to bidirectionally attenuate or enhance nociception, suggesting a potential role for NAc in setting nociceptive sensitivity.

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Figures

Figure 1
Figure 1
NAc injection sites. Filled circles indicate —on-site injections; open circles indicate —off-site injections. All injections were bilateral; some injection sites overlap others. Numbers indicate distance rostral to bregma (mm). (Adapted from (Paxinos and Watson, 1986).
Figure 2
Figure 2
The effect of intra-NAc lidocaine administration on the JOR. QX-314 (333 ng, 0.3 μl per side), a quaternary analog of the local anesthetic lidocaine, or vehicle (same volume) was administered into NAc. QX-314 was also administered off-site (same dose and volume). On-site, but not off-site, QX-314 significantly attenuated the JOR at all post-administration time points, indicating that in otherwise untreated animals NAc produces a pronociceptive signal, and that suppression of this signal by lidocaine results in antinociception as revealed by attenuation of the JOR.
Figure 3
Figure 3
Effect of QX-314 on analgesia induced by intra-NAc administration of exogenous opioids. The μ-opioid receptor agonist DAMGO (—Dgo" 150 ng) and the δ-opioid receptor agonist DPDPE (—Dpdpe 150 ng) were combined and administered to NAc (n = 5). The JOR was recorded thirty minutes later and then QX-314 (333 ng) was administered into the same site. Although QX-314 alone can attenuate the JOR (Fig. 2), its effect was occluded when administered subsequently to the opioid combination, suggesting that these two treatments produce analgesia by the same NAc mechanism, that is, attenuation of efferent activity.
Figure 4
Figure 4
The effect of intra-NAc kainate administration on the JOR. The excitatory amino acid agonist kainate (63 ng, 0.3 μl per side) or vehicle (same volume) was administered into NAc. Kainate significantly enhanced the JOR (shown as negative numbers on the y-axis) for at least thirty minutes after administration (asterisks), supporting the suggestion that NAc signals can modulate nociception bidirectionally; that is, can produce enhancement as well as attenuation.
Figure 5
Figure 5
The effect intra-NAc opioid antagonists on antinociception induced by i.t. DAMGO administration. I.t. DAMGO (7.5 μg, 15 μl), a selective μ-opioid receptor antagonist, alone attenuated the JOR, an effect that was blocked by prior administration of CTOP (1 μg, 0.3 μl per side), a selective μ-opioid receptor antagonist, or naltrindole (1 μg, 0.3 μl per side), a selective δ-opioid receptor antagonist, but not their vehicles (same volumes).
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