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Targeting the Nav1.8 ion channel engenders sex-specific responses in lysophosphatidic acid–induced joint neuropathy

O'Brien, Melissa S.a,b; Philpott, Holly T.A.a,b; McDougall, Jason J.a,b,*

doi: 10.1097/j.pain.0000000000001399
Research Paper

Joint neuropathic pain occurs in a subset of arthritis patients, and lysophosphatidic acid (LPA) has been implicated as a mediator of joint neuropathy. The mechanism by which LPA promotes neuropathic pain is unknown but may be related to altered signalling of the voltage-gated sodium channel Nav1.8 located on nociceptors. Because arthritis and neuropathic pain are more prevalent in females, this study aimed to explore potential sex differences in the development of LPA-induced joint neuropathy and whether Nav1.8 played a role in the associated neuropathic pain. Joint neuropathy was induced in male and female Wistar rats (179-284 g) by intra-articular injection of 50-µg LPA. Pain behaviour was assessed over 21 days using von Frey hair algesiometry. On day 21, electrophysiological recordings of joint primary afferents were conducted to measure peripheral sensitisation. Saphenous nerve morphology and expression of the nerve-damage marker ATF3 and Nav1.8 in ipsilateral dorsal root ganglions were compared on the basis of sex. The analgesic properties of the selective Nav1.8 antagonist A-803467 was determined in pain behaviour and electrophysiology experiments. Females developed more severe mechanical allodynia than males after LPA treatment. Lysophosphatidic acid caused more pronounced demyelination of the saphenous nerve in females, but no sex differences were observed in the expression of ATF3 or Nav1.8 in dorsal root ganglion neurones. Blockade of Nav1.8 channels with A-803467 resulted in a decrease in joint mechanosensitivity and secondary allodynia with females exhibiting a greater response. These findings suggest that LPA has sex-specific effects on joint neuropathy and Nav1.8 gating, which should be considered when treating neuropathic arthritis patients.

Joint neuropathy and resulting neuropathic pain were more pronounced in females. Nav1.8 ion channel blockade was also more effective in females than males.

Departments of aPharmacology and

bAnaesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada

Corresponding author. Address: Departments of Pharmacology and Anaesthesia, Pain Management and Perioperative Medicine, Dalhousie University, 5850 College St, Halifax, NS B3H 4R2, Canada. Tel.: (902) 494-4066; fax: (902) 494-1388. E-mail address: (J.J. McDougall).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received April 10, 2018

Received in revised form September 04, 2018

Accepted September 06, 2018

© 2019 International Association for the Study of Pain
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