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Dopaminergic neurons of the mesolimbic system originate from cell bodies within the ventral tegmental area (VTA) and project primarily to the ventral striatum/nucleus accumbens (NAc). Morgan and Franklin (1990) first demonstrated that targeted depletion of mesolimbic dopamine by 6-hydroxydopamine (6-OHDA) results in the abolition of analgesia produced by systemic morphine and D-amphetamine in the formalin test in rats. In the tail-flick test, however, only the analgesia produced by D-amphetamine, which evokes the release of dopamine while simultaneously inhibiting its reuptake, was abolished. The analgesic action of morphine was preserved. Saade et al. (1997) reported that 6-OHDA lesions of the striatum and VTA significantly increased pain sensitivity, as demonstrated by reduced latencies of multiple nociceptive reflexes and increased autonomy following chronic sciatic nerve transaction. Sotres-Bayon et al. (2001) also demonstrated that VTA lesions enhanced autotomy; electrical stimulation of the VTA produced analgesia. Takeda et al. (2005) reported that 6-OHDA lesions of the mesostriatal pathway resulted in immediate and lasting hypersensitivity to mechanical stimulation.
The following summarizes an extensive series of studies by Altier and Stewart (1999) on the contribution of mesolimbic dopamine to analgesia. Both substance P (SP) and μ-opioids activate dopaminergic neurons and local administration of the SP analog DiMe-C7 into the VTA attenuates pain responses in the formalin test, without altering tail-flick latencies. The same is true for local infusion of amphetamine. Although systemic naltrexone did not reverse these analgesic effects, pretreatment by NAc injection with a variety of dopamine antagonists did reduce the analgesia induced by intra-VTA infusions of the DiMe-C7 or morphine and intra-NAc infusion of amphetamine. A subsequent investigation by Taylor et al. (2003) demonstrated that selective activation of D2-receptors by microinfusion of quinpirole in the NAc dose-dependently inhibited tonic pain, while local infusion of a D1-selective agonist failed to produce analgesia.
In summary, these results indicate that activation of mesolimbic dopamine neurons contributes to suppression of tonic pain, presumably via activation of postsynaptic D2 receptors in the nucleus accumbens.
Pain 120 (2006) 230-234
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