Attenuated dopamine receptor signaling in nucleus accumbens core in a rat model of chemically-induced neuropathy

Neuropharmacology. 2020 Apr:166:107935. doi: 10.1016/j.neuropharm.2020.107935. Epub 2020 Jan 7.

Abstract

Neuropathy is major source of chronic pain that can be caused by mechanically or chemically induced nerve injury. Intraplantar formalin injection produces local necrosis over a two-week period and has been used to model neuropathy in rats. To determine whether neuropathy alters dopamine (DA) receptor responsiveness in mesolimbic brain regions, we examined dopamine D1-like and D2-like receptor (D1/2R) signaling and expression in male rats 14 days after bilateral intraplantar formalin injections into both rear paws. D2R-mediated G-protein activation and expression of the D2R long, but not short, isoform were reduced in nucleus accumbens (NAc) core, but not in NAc shell, caudate-putamen or ventral tegmental area of formalin- compared to saline-treated rats. In addition, D1R-stimulated adenylyl cyclase activity was also reduced in NAc core, but not in NAc shell or prefrontal cortex, of formalin-treated rats, whereas D1R expression was unaffected. Other proteins involved in dopamine neurotransmission, including dopamine uptake transporter and tyrosine hydroxylase, were unaffected by formalin treatment. In behavioral tests, the potency of a D2R agonist to suppress intracranial self-stimulation (ICSS) was decreased in formalin-treated rats, whereas D1R agonist effects were not altered. The combination of reduced D2R expression and signaling in NAc core with reduced suppression of ICSS responding by a D2R agonist suggest a reduction in D2 autoreceptor function. Altogether, these results indicate that intraplantar formalin produces attenuation of highly specific DA receptor signaling processes in NAc core of male rats and suggest the development of a neuropathy-induced allostatic state in both pre- and post-synaptic DA receptor function.

Keywords: Adenylyl cyclase; Autoreceptor; Dopamine; G-protein; Neuropathic pain; Nucleus accumbens.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Disease Models, Animal
  • Dopamine Agonists / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Formaldehyde / toxicity*
  • Male
  • Neuralgia / chemically induced
  • Neuralgia / metabolism*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*

Substances

  • DRD2 protein, rat
  • Dopamine Agonists
  • Dopamine Antagonists
  • Drd1 protein, rat
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Formaldehyde