title: Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury.
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 (1.5mg/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 microg/50 microl) and the highly selective MOR antagonist CTAP (5.5 microg/50 microl). However, this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1 microg/50 microl). 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 microg/50 microl) 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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, 720 Rutland Avenue, Ross 350, Baltimore, MD 21205, USA Department of Neurosurgery, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Johanek
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Hartke
authors.forename: Beom
authors.initials: B
authors.lastname: Shim
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
authors.forename: Matthias
authors.initials: M
authors.lastname: Ringkamp
authors.forename: Richard A
authors.initials: RA
authors.lastname: Meyer
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D008139:Loperamide / Q000494:pharmacology / Q000627:therapeutic use; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000502:physiology; D008297:Male; D009437:Neuralgia / Q000503:physiopathology / Q000517:prevention & control*; D017933:Peripheral Nervous System / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000502:physiology; D013127:Spinal Nerves / Q000187:drug effects* / Q000293:injuries* / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D008139:Loperamide