title: Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats.
abstract: Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 μg/50 μL intraplantarly) and D-Ala(2)-MePhe(4)-Glyol(5) enkephalin (300 μg/50 μL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5mg/kg intraperitoneally) and MK-801 (0.2mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3mg/kg subcutaneously), but not loperamide (3mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca(2+)]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 μM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide's inhibition of KCl-elicited [Ca(2+)]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug administration.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, Columbia, SC, USA Department of Clinical Pharmacology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China Department of Anesthesiology and Pain Medicine, School of Medicine, Wonkwang University, Ikscan, South Korea Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: Shao-Qiu
authors.initials: SQ
authors.lastname: He
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.forename: Federico M
authors.initials: FM
authors.lastname: Perez
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Ronen
authors.initials: R
authors.lastname: Shechter
authors.forename: Yong-Kwan
authors.initials: YK
authors.lastname: Cheong
authors.forename: Alene F
authors.initials: AF
authors.lastname: Carteret
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Sweitzer
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy*; D007150:Immunohistochemistry; D008026:Ligation; D008139:Loperamide / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects; D013127:Spinal Nerves / Q000293:injuries*
chemical_list: D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D016291:Dizocilpine Maleate; D008139:Loperamide; D002118:Calcium
keywords: Nerve injury; Neuropathic pain; Peripheral opioid receptor; Rats; Tolerance