Abstract
Based on animal studies and some indirect clinical evidence, dopamine has been suggested to have anti-nociceptive effects. Here, we investigated directly the effects of increased and decreased availability of extracellular dopamine on pain perception in healthy volunteers. In Study 1, participants ingested, in separate sessions, a placebo and a low dose of the centrally acting D2-receptor antagonist sulpiride, intended to increase synaptic dopamine via predominant pre-synaptic blockade. No effects were seen on thermal pain thresholds, tolerance, or temporal summation. Study 2 used the acute phenylalanine and tyrosine depletion (APTD) method to transiently decrease dopamine availability. In one session participants ingested a mixture that depletes the dopamine amino acid precursors, phenylalanine and tyrosine. In the other session they ingested a nutritionally balanced control mixture. APTD led to a small mood-lowering response following aversive thermal stimulation, but had no effects on the perception of cold, warm, or pain stimuli. In both studies the experimental manipulation of dopaminergic neurotransmission was successful as indicated by manipulation checks. The results contradict proposals that dopamine has direct anti-nociceptive effects in acute experimental pain. Based on dopamine’s well-known role in reward processing, we hypothesize that also in the context of pain, dopamine acts on stimulus salience and might play a role in the initiation of avoidance behavior rather than having direct antinociceptive effects in acute experimental pain.
Highlights
Dopamine has well described and oft-cited roles in motivational states, reward processing, and motor functions
Replicating earlier results, the APTD procedure resulted in a reduction of plasma phenylalanine and tyrosine levels, indicated by an interaction of ‘APTD’ and ‘testing’
While the APTD mixture resulted in a decrease of phenylalanine (-88.77%) and tyrosine (-85.47%) post ingestion, the balanced mixture resulted in an increase of the two amino acids as expected
Summary
Dopamine has well described and oft-cited roles in motivational states, reward processing, and motor functions (see 1,2 for review). Dopamine plays a role in the processing of nociceptive stimuli. It has been hypothesized that dopamine has direct anti-nociceptive effects [3,4,5,6,7]. This hypothesis is based on three main lines of evidence: rodent studies, clinical data, and genetic associations. Typically using interventions such as intrathecal or intracerebral microinjections of receptor a- and antagonists, indicate that effects of dopamine on nociceptive processing are mainly mediated by striatal dopaminergic D2-receptors Activation or inhibition of striatal D1receptors by microinjections of receptor agonists or antagonists has no effects on nociceptive processing [8,9,10]. Antinociceptive effects of D2-receptor activation and pronociceptive effects of D2-receptor inhibition have been shown in tonic pain models such as the writhing and formalin tests, in deafferentation and neuropathic pain models (e.g. [11,12,13,14]), and in phasic pain models using thermal and mechanical stimuli, including the tail flick, hot plate or paw pressure test
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