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

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

Research output: Contribution to journalArticle

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 (0.3-10 mg/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 (1.5 mg/kg, s.c.) was blocked by systemic pretreatment with either naloxone hydrochloride (10 mg/kg, i.p.) or methyl-naltrexone (5 mg/kg, i.p.), a peripherally acting MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-naltrexone (43.5 μg/50 μl) and the highly selective MOR antagonist CTAP (5.5 μg/50 μl). However, this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1 μg/50 μl). 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 (10-100 μg/50 μl) 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.

Original languageEnglish (US)
Pages (from-to)318-329
Number of pages12
JournalPain
Volume138
Issue number2
DOIs
StatePublished - Aug 31 2008

Fingerprint

Loperamide
Spinal Injuries
Spinal Nerves
mu Opioid Receptor
Neuralgia
Ligation
Narcotic Antagonists
Naltrexone
naltrindole
Hyperalgesia
delta Opioid Receptor
Naloxone
Opioid Analgesics
Theoretical Models
Central Nervous System
Injections
Wounds and Injuries

Keywords

  • Loperamide
  • Mechanical allodynia
  • Mu-opioid receptor
  • Nerve injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Neurology
  • Neuroscience(all)
  • Pharmacology
  • Clinical Psychology

Cite this

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; Raja, Srinivasa Naga.

In: Pain, Vol. 138, No. 2, 31.08.2008, p. 318-329.

Research output: Contribution to journalArticle

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AB - 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 (0.3-10 mg/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 (1.5 mg/kg, s.c.) was blocked by systemic pretreatment with either naloxone hydrochloride (10 mg/kg, i.p.) or methyl-naltrexone (5 mg/kg, i.p.), a peripherally acting MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-naltrexone (43.5 μg/50 μl) and the highly selective MOR antagonist CTAP (5.5 μg/50 μl). However, this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1 μg/50 μl). 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 (10-100 μg/50 μl) 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.

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