Descending modulation of neuropathic hypersensitivity by dopamine D2 receptors in or adjacent to the hypothalamic A11 cell group.
We determined the role of the dopamine D2 receptor in or adjacent to the dopaminergic A11 cell group in descending modulation of neuropathic hypersensitivity. Moreover, we determined the spinal neurotransmitter receptors mediating the modulatory effect. Neuropathy was produced by spinal nerve ligation in the rat that had a chronic cannula for drug delivery into A11 or a control site in the locus coeruleus, and a catheter for spinal drug delivery. Hypersensitivity was assessed by a withdrawal response to monofilaments. Quinpirole (a dopamine D2/D3 receptor agonist) in A11 attenuated hypersensitivity, without influencing thermal nociception in the uninjured tail. Quinpirole in the locus coeruleus failed to influence hypersensitivity. L-741,626 (a dopamine D2 receptor antagonist), raclopride (a dopamine D2/D3 receptor antagonist) and bicuculline (a GABA(A) receptor antagonist) in A11 reversed the antihypersensitivity effect of quinpirole. Raclopride or bicuculline alone in A11 had no effects, whereas muscimol (a GABA(A) receptor agonist) alone in A11 suppressed hypersensitivity. Spinal administration of atipamezole (an alpha(2)-adrenoceptor antagonist) or marginally also WAY-100635 (a 5-HT(1A) receptor antagonist), but not raclopride or bicuculline, reduced the antihypersensitivity effect induced by quinpirole in A11. Electrical stimulation of A11 produced thermal antinociception following intrathecal administration of saline but not raclopride. The results indicate that activation of the dopamine D2 receptor in A11 may selectively suppress neuropathic hypersensitivity, due to mechanisms that involve GABA(A) receptors in the hypothalamus and descending noradrenergic pathways acting on spinal alpha(2)-adrenoceptors, possibly together with a slight contribution of descending serotoninergic pathways acting on spinal 5-HT(1A) receptors.
Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland.
Hong
H
Wei
Hanna
H
Viisanen
Antti
A
Pertovaara
D000818:Animals; D065127:Dopamine D2 Receptor Antagonists; D004525:Efferent Pathways / Q000503:physiopathology*; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology*; D010812:Physical Stimulation; D051381:Rats; D011919:Rats, Inbred Strains; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism
D065127:Dopamine D2 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D044282:Receptor, Serotonin, 5-HT1A