Dopamine receptor D2, but not D1, mediates descending dopaminergic pathway–produced analgesic effect in a trigeminal neuropathic pain mouse model

Abstract

Neuropathic pain represents a challenge to clinicians, because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain via the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.

Role of Descending Dopaminergic Pathways in Pain Modulation

“…It has been reported that dopamine receptors D1/D5 engage the mechanism of spinal hyperalgesic priming and maintenance of pathological pain plasticity and that D1/D5 agonists induce mechanical hypersensitivity [4]. Our recently published work demonstrates that activation of dopaminergic neurons in the hypothalamic A11 nucleus attenuates peripheral nerve injury-induced neuropathic pain, which is mediated by D2-like dopamine receptors [31]. Taylor and colleagues found that microinjection of selective D2-like dopamine receptor agonist quinpirole in the NAc inhibits formalin-induced persistent nociception in the hind paw [40].…”

“…However, a recent study reported that although dopamine appears to affect expectations and desires, dopamine changes in the brain do not affect emotional pain in patients with chronic neuropathic pain after placebo intervention [47]. Using von Frey and conditioned place preference tests, we observed that activation of the descending dopaminergic pathway from hypothalamic A11 nucleus to Sp5C inhibits both sensory and emotional components of pain induced by peripheral nerve injury [31].…”

“…Using D1-Cre and D2-Cre transgenic mice, we observed that both D1 and D2 receptors are expressed in the Sp5C and the two types of dopamine receptors mostly distribute in different neurons, suggesting that dopamine may exert different pain regulation by binding to different receptors. In a trigeminal neuropathic pain animal model, induced by chronic constriction injury of the infraorbital nerve, we observed that optogenetic excitation or chemogenetic activation of the descending dopaminergic pathway from the hypothalamic A11 to Sp5C alleviates the neuropathic pain via activation of D2 receptors in the Sp5C [31]. Moreover, 6-OHDA-produced A11 lesion of dopaminergic neurons exacerbates such pain, suggesting that the descending A11-Sp5C dopaminergic pathway is paininhibitory [31].…”

“…In rodent studies, the expression of D1 and D2 receptors in the contralateral NAc is down-regulated on day 28 of chronic neuropathic pain [30]. We recently reported that the D2 receptor plays a critical role in the descending inhibition of trigeminal neuropathic pain [31]. Therefore, the dopamine receptors could be indispensable in regulating neuronal excitability.…”

“…It has been reported that the descending dopaminergic pathway can send direct inhibitory projections to the target areas [38]. For instance, the dopaminergic neurons in the hypothalamic A11 nucleus directly project to the Sp5C and excitation of the descending dopaminergic neurons inhibits orofacial neuropathic pain [31]. The A11 dopaminergic neurons also send direct inhibitory projections to the spinal dorsal horn, which may be the sole source of spinal dopamine [38].…”