Central high mobility group box-1 induces mechanical hypersensitivity
with spinal microglial activation in a mouse model of hemi-Parkinson's
Background and Purpose: Parkinson’s disease (PD) patients often complain
of pain, but this problem has been neglected and is poorly understood.
High mobility group box-1 (HMGB1), an alarmin/damage-associated
molecular patterns protein, is increased in the cerebrospinal fluid in
PD patients. However, little is known of the relationship between HMGB1
and pain associated with PD. Here, we investigated the role of central
HMGB1 in the regulation of nociceptive hypersensitivity in a mouse model
of PD. Experimental Approach: Male ddY mice were microinjected
unilaterally with 6-hydroxydopamine (6OHDA) into the striatum. These
hemi-PD mice were treated with anti-HMGB1 neutralizing antibody (nAb; 10
µg in 10 µL) by intranasal (i.n.) administration. The mechanical
hypersensitivity of the hind paws was evaluated with the von Frey test.
Spinal microglial activity was analyzed by immunostaining for ionized
calcium-binding adapter molecule 1. Key Results: The 6OHDA-administered
mice displayed unilateral loss of dopamine neurons in the substantia
nigra and mechanical hypersensitivity in both hind paws. Moreover,
spinal microglia were activated in these hemi-PD mice. Twenty-eight days
after the 6OHDA injections, repeated i.n., but not systemic, treatment
with anti-HMGB1 nAb inhibited the bilateral mechanical hypersensitivity
and spinal microglial activation. However, the anti-HMGB1 nAb did not
ameliorate the dopamine neuron loss. Moreover, intracerebroventricular
injection with recombinant HMGB1 induced mechanical hypersensitivity.
Conclusions and Implications: These findings indicate that HMGB1 is
involved in the maintenance of nociceptive symptoms in hemi-PD mice via
spinal microglial activation. Therefore, central HMGB1 may have
potential as a therapeutic target for pain associated with PD.