Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson’s Disease

Abstract

In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain.

Bilateral Parkinson’s disease model rats exhibit hyperalgesia to subcutaneous formalin administration into the vibrissa pad

“…The change of nociception was reported in the studies using unilateral PD model rats [4–6]. And, mechanical allodynia or hypersensitivity were reported in the studies using bilateral PD model rats [7–9]. Our results are consistent of results of these studies in that the change of nociception occurred.…”

“…These studies, including ours, involved the use of unilateral PD model rats. In few studies, nociception has been examined with the usage of bilateral PD model rats [7–9]. Because idiopathic PD is bilateral, bilateral PD model rats are more closely to the pathological condition in humans [10].…”

Pramipexole and tolcapone alleviate thermal and mechanical nociception in naive rats.

“…Taylor and colleagues found that bilateral microinjection of the D 2 -like receptor agonist quinpirole in nucleus accumbens inhibits persistent nociception in the formalin test in rats. 15 In experimental conditions the analgesic effect of pramipexole is demonstrated in animals with artificially-induced PD 13,16 but not in naïve rats. Cao LF et al found that pramipexole reduces thermal, but not mechanical pain hypersensitivity in rats with 6-OHD-induced model of PD.…”

“…12 Pramipexole is D 2 /D 3 dopamine receptor agonist found to inhibit thermal hypersensitivity in rats with 6-hydroxydopamine (6-OHDA) model of PD. 13 Clinical trials demonstrated that this drug decreases pain in patients with fibromyalgia. 14 Tolcapone is an inhibitor of dopamine metabolising enzyme catechol-O-methyltransferase (COMT).…”

Effects of tapentadol on pain, motor symptoms and cognitive functions in Parkinson’s disease

“… 16 – 19 Also, because of its unique noradrenergic features, tapentadol may improve pain in PD by restoring the spinal noradrenergic inhibitory tone. 15 , 20 , 21 …”