Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn

Abstract

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C-fiber-evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2-like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2-like receptors at the level of superficial medullary dorsal horn. Such dopamine-dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms--spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these.

Synaptic upregulation and superadditive interaction of dopamine D2- and μ-opioid receptors after peripheral nerve injury

“…Such a depressant effect agrees with findings from previous behavioral studies [8,9,46] as well as intracellular and extracellular recordings in the dorsal horn and trigeminocervical complex [19,24,40,64,65]. In this study, we show, for the first time, that the efficacy of D2R in modulating spinal excitation to noxious input is enhanced after nerve injury.…”

“…Dopamine-like immunoreactivity is profusely distributed throughout the gray matter of the spinal dorsal horn [31], and all 5 G-protein-coupled receptor types through which synaptic effects of dopamine are exerted, namely D1 through D5, have been found in the spinal cord [12,19,22,44,61,68,77,78]. The A11 region in the dorsal posterior hypothalamus is the sole known source of dopaminergic innervation to the dorsal horn [30,62], and diencephalospinal projections arising from these neurons inhibit nociceptive transmission at the dorsal horn level, primarily via D2 receptors [19,24,40,64,65]. Studies show that D2R may establish complex interactions with opioid receptors, as D2R-agonists have so far been linked to both facilitation [55] and attenuation [34] of opioid analgesia, whereas D2R-blockade may reportedly potentiate [60] or diminish [55] MOR analgesia.…”

Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion

“…Using in vivo patch-clamp analysis, Taniguchi et al (2011) reported that dopamine produces direct inhibitory effects on substantia gelatinosa neurons in the spinal cord in response to both noxious and innocuous stimulation of the skin. A reduction or facilitation of trigeminal nociceptive behavior induced by a formalin injection is observed with the local administration of a D2-like receptor agonist or antagonist, respectively, suggesting the existence of a tonic descending dopaminergic control of nociceptive transmission mediated via D2-like receptors in the medullary dorsal horn (Lapirot et al, 2011). The aforementioned results suggest that the hyperalgesic response to the formalin injection in the present study is attributable to the disinhibition of descending dopaminergic control caused by neonatal dopamine depletion.…”

“…The descending noradrenergic and serotonergic pathways to the spinal cord modulate the activity of nociceptive neurons (Jones, 1991;Millan, 2002;Pertovaara, 2006;Saade´and Jabbur, 2008;Heinricher et al, 2009;Wu et al, 2010;Bardin, 2011). Descending dopaminergic controls of nociceptive transmission in the spinal and medullary dorsal horn have recently been reported (Lapirot et al, 2011;Taniguchi et al, 2011;Kawamoto et al, 2012). Using in vivo patch-clamp analysis, Taniguchi et al (2011) reported that dopamine produces direct inhibitory effects on substantia gelatinosa neurons in the spinal cord in response to both noxious and innocuous stimulation of the skin.…”

Catecholaminergic connectivity to the inner ear, central auditory, and vocal motor circuitry in the plainfin midshipman fish porichthys notatus

“…This sexual dimorphism is an androgen receptor-dependent mechanism, organized by differential exposure to androgens perinatally (Pappas et al, 2010). The function of DA in this area is thought to modulate sensory (including nociception) information and motor function (Barriere et al, 2004;Lapirot et al, 2011). Interestingly, as seen in zebrafish, single A11 neurons in mammals are known to have both descending spinal as well as ascending telencephalic projections.…”