Striatal delta opioid receptor binding in experimental models of Parkinson's disease and dyskinesia

Abstract

Enhanced delta opioid receptor transmission may represent an endogenous compensatory mechanism in parkinsonism to reduce the activity of the indirect striatopallidal pathway following dopamine depletion. Furthermore, increased delta opioid receptor transmission may be causative in the production of dyskinesia following repeated dopaminergic treatment in Parkinson's disease. The present study employed radioligand receptor autoradiography, using [3H]naltrindole, a ligand selective for the delta opioid receptor, to assess delta opioid receptor binding sites in forebrain regions of reserpine-treated rats, and in parkinsonian nondyskinetic, and dyskinetic MPTP-lesioned macaques. In reserpine-treated animals, specific delta opioid binding was increased in premotor cortex (+30%), sensorimotor striatum (+20%), and associative striatum (+17%) rostrally, but was not changed in caudal forebrain. In contrast, delta opioid receptor binding was not significantly altered at any region analyzed, in either nondyskinetic or dyskinetic, MPTP-lesioned macaques, compared to normal. These results suggest that transient changes in delta opioid receptor binding may occur in motor circuits following acute dopamine depletion. However, in the more chronic MPTP-lesioned macaque model, simple changes in delta opioid receptor number or affinity are unlikely to contribute to mechanisms for abnormal opioid transmission in Parkinson's disease and dyskinesia.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…However, enhanced signaling at d receptors appears to be a mechanism by which they could contribute to the expression of LID. Thus, in the MPTP-lesioned NHP killed in the on-state, in no brain region assessed were d-opioid receptor levels significantly different to those in control animals, regardless of L-DOPA administration (Aubert et al, 2007;Hallett and Brotchie, 2007). However, d-receptor levels were increased in both the motor and premotor cortex of dyskinetic 6-OHDA-lesioned rats killed in the off-state compared with nondyskinetic animals (Johansson et al, 2001).…”

δ-Opioid Receptor Function in the Dorsal Striatum Plays a Role in High Levels of Ethanol Consumption in Rats

“…Furthermore, naltrindole (20 mg/kg, s.c.) selectively antagonized analgesia in mice elicited by the DOP-R agonist, DSLET (D-Ser2-Leu5-Enkephalin-Thr6), but not analgesia elicited by morphine or U50488H (Portoghese et al, 1988). Naltrindole has since been used extensively both in vitro and in vivo due to its high selectivity for the DOP-R ( Krishnan-Sarin et al, 1995a;Saitoh et al, 2004Saitoh et al, , 2005Perrine et al, 2006;Hallett and Brotchie, 2007). SNC80 and TAN67 were used since these small molecule compounds are reported to be very selective for the DOP-R (Bilsky et al, 1995;Kamei et al, 1995;Calderon et al, 1997;Tseng et al, 1997) compared to DOP-R peptide agonists, such as DPDPE, which are less selective for the DOP-R with activity at the MOP-R in the micromolar range (Scherrer et al, 2004) (Bilsky et al, 1995).…”

Functional Neuroimaging in Parkinson's Disease

“…These include the opioid system, which acts as a modulator of dopamine and a cotransmitter within GABAergic neurons (Fox et al 2006;Hallett and Brotchie 2007), the adenosine system (Calon et al 2004), the serotonergic system (Carta et al 2007;Carlsson et al 2009), and the a2 adrenergic system (Fox et al 2001;Rascol et al 2001). Piccini et al (1997) found reduced binding of [ 11 C]diphrenorphine (a nonselective marker of opioid receptors) in the striatum, thalamus, and anterior cingulate of PD patients with LID compared to without.…”