Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury

Guan, Yun; Johanek, Lisa M.; Hartke, Timothy V.; Shim, Beom; Tao, Yuan-Xiang; Ringkamp, Matthias; Meyer, Richard A.; Raja, Srinivasa N.

doi:10.1016/j.pain.2008.01.004

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Volume 138, Issue 2 , Pages 318-329, 31 August 2008

Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury

Yun Guan
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, 720 Rutland Avenue, Ross 350, Baltimore, MD 21205, USA
- Corresponding author. Tel.: +1 410 502 5511; fax: +1 410 614 2109.
Lisa M. Johanek
- Department of Neurosurgery, The Johns Hopkins University, Baltimore, MD 21205, USA
Timothy V. Hartke
- Department of Neurosurgery, The Johns Hopkins University, Baltimore, MD 21205, USA
Beom Shim
- Department of Neurosurgery, The Johns Hopkins University, Baltimore, MD 21205, USA
Yuan-Xiang Tao
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, 720 Rutland Avenue, Ross 350, Baltimore, MD 21205, USA
Matthias Ringkamp
- Department of Neurosurgery, The Johns Hopkins University, Baltimore, MD 21205, USA
Richard A. Meyer
- Department of Neurosurgery, The Johns Hopkins University, Baltimore, MD 21205, USA
Srinivasa N. Raja
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, 720 Rutland Avenue, Ross 350, Baltimore, MD 21205, USA

Received 5 September 2007; received in revised form 6 December 2007; accepted 7 January 2008. published online 14 February 2008.

Abstract

Studies in experimental models and controlled patient trials indicate that opioids are effective in managing neuropathic pain. However, side effects secondary to their central nervous system actions present barriers to their clinical use. Therefore, we examined whether activation of the peripheral mu-opioid receptors (MORs) could effectively alleviate neuropathic pain in rats after L5 spinal nerve ligation (SNL). Systemic loperamide hydrochloride (0.3–10mg/kg, s.c.), a peripherally acting MOR-preferring agonist, dose-dependently reversed the mechanical allodynia at day 7 post-SNL. This anti-allodynic effect produced by systemic loperamide (1.5mg/kg, s.c.) was blocked by systemic pretreatment with either naloxone hydrochloride (10mg/kg, i.p.) or methyl-naltrexone (5mg/kg, i.p.), a peripherally acting MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-naltrexone (43.5μg/50μl) and the highly selective MOR antagonist CTAP (5.5μg/50μl). However, this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1μg/50μl). The anti-allodynic potency of systemic loperamide varied with time after nerve injury, with similar potency at days 7, 28, and 42 post-SNL, but reduced potency at day 14 post-SNL. Ipsilateral intraplantar injection of loperamide also dose-dependently (10–100μg/50μl) reversed mechanical allodynia on day 7 post-SNL. We suggest that loperamide can effectively attenuate neuropathic pain, primarily through activation of peripheral MORs in local tissue. Therefore, peripherally acting MOR agonists may represent a promising therapeutic approach for alleviating neuropathic pain.