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Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone

Hughes, Sama; Hickey, Louisea; Donaldson, Lucy F.b; Lumb, Bridget M.a,*; Pickering, Anthony E.a

doi: 10.1097/01.j.pain.0000460313.73358.31
Research Paper
Global Year
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The descending noradrenergic (NAergic) projection to the spinal cord forms part of an endogenous analgesic system. After nerve injury, a localised failure in this compensatory system has been implicated as a permissive factor in the development of neuropathic sensitisation. We investigated whether restoring descending NAergic tone with intrathecal reboxetine can oppose the development of the neuropathic pain phenotype after tibial nerve transection (TNT). Rats had a lumbar intrathecal catheter implanted at the time of nerve injury for administration of reboxetine (10 μg) in both acute and chronic dosing experiments. In acute dosing experiments, both intrathecal and systemic (30 mg/kg) reboxetine partially reversed mechanical allodynia. This antiallodynic effect of intrathecal reboxetine was blocked by prior administration of yohimbine (α2-adrenoceptor antagonist, 30 μg) but not by prazosin (α1-adrenoceptor antagonist, 30 μg) or propranolol (β-adrenoceptor antagonist, 100 μg). Chronic intrathecal reboxetine (10 μg, intrathecally, twice daily for 2 weeks) suppressed the development of cold and mechanical allodynia. Nerve-injured animals demonstrated a place preference for intrathecal reboxetine, suggesting that it also reduced spontaneous pain. In contrast, an equivalent antiallodynic dose of systemic reboxetine (30 mg/kg) was aversive in both naive and TNT rats. On cessation of chronic intrathecal reboxetine, there was a gradual development of allodynic sensitisation that was indistinguishable from control TNT animals by 7 days after the end of dosing. Our results suggest that pharmacological restoration of spinal NAergic tone with intrathecal reboxetine can suppress both allodynia and spontaneous pain in the TNT model.

Restoration of endogenous descending noradrenergic tone protects against the development of neuropathic sensitisation after peripheral nerve injury.

aSchool of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom

bArthritis Research UK Pain Centre and School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham, United Kingdom

Corresponding author. Address: School of Physiology and Pharmacology, Medical Sciences Building, University Walk, University of Bristol, BS8 1TD, United Kingdom. Tel.: 0117 331 2313; fax: +44 (0)117 33 11889. E-mail address: (B. M. Lumb).

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

This is an open access article distributed under the Creative Commons Attribution- Non Commercial License, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially.

Received April 17, 2014

Received in revised form October 10, 2014

Accepted November 21, 2014

© 2015 International Association for the Study of Pain
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