title: Anti-allodynic actions of intravenous opioids in the nerve injured rat: potential utility of heroin and dihydroetorphine against neuropathic pain.
abstract: Neuropathic pain has been suggested to be resistant to treatment with opiates. Such perceived lack of opioid responsiveness may be due to the dose-range over which specific opioid compounds have been studied as well as the efficacy of these compounds. Dihydroetorphine is a novel opiate that demonstrates significantly greater analgesic potency compared to morphine, and which also demonstrates diminished capacity for producing physical dependence in laboratory animals. The present study compared the intravenous (i.v.) efficacy, potency and duration of action of dihydroetorphine, fentanyl, heroin and morphine in producing anti-allodynic actions in a rat model of neuropathic pain (ligation of the L5/L6 nerve roots). All compounds produced significant anti-allodynic activity with dihydroetorphine being the most potent (A50 of 0.2 microg kg(-1), i.v.). Morphine was approximately 7440 times less potent than dihydroetorphine while heroin and fentanyl were approximately 163.5 and 6.9 times less potent in producing anti-allodynic actions. Dihydroetorphine also showed a maximal effect at 0.6 microg kg(-1) in all animals tested, while 100 microg kg(-1) was required for heroin to produce a maximal effect. Fentanyl and morphine did not elicit a maximum anti-allodynic response (74 and 76% maximum possible effect (%MPE), respectively). As expected, fentanyl showed a relatively brief duration of action (approximately 20 min at the highest tested dose), while dihydroetorphine and morphine demonstrated anti-allodynic actions for up to 45 min. Heroin had the longest duration of action, producing significant anti-allodynic effects for up to 90 min. These data show that dihydroetorphine and heroin produce potent and long-lasting anti-allodynic actions in this model. Additionally, in contrast to morphine and fentanyl, both dihydroetorphine and heroin were able to achieve a maximal response. The remarkable potency, maximal efficacy and duration of action of these compounds, particularly dihydroetorphine, suggests that these compounds may warrant further examination as potential therapeutic treatments for neuropathic pain states.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA. tjmartin@wfubmc.edu
authors.forename: T J
authors.initials: TJ
authors.lastname: Martin
authors.forename: C T
authors.initials: CT
authors.lastname: Hairston
authors.forename: P O
authors.initials: PO
authors.lastname: Lutz
authors.forename: L S
authors.initials: LS
authors.lastname: Harris
authors.forename: F
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D004341:Drug Evaluation; D005048:Etorphine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005283:Fentanyl / Q000627:therapeutic use; D003932:Heroin / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008026:Ligation; D008297:Male; D009020:Morphine / Q000627:therapeutic use; D009408:Nerve Compression Syndromes; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D011916:Rats, Inbred F344; D013127:Spinal Nerves / Q000293:injuries*
chemical_list: D000701:Analgesics, Opioid; D005048:Etorphine; D003932:Heroin; D009020:Morphine; C034765:18,19-dihydroetorphine; D005283:Fentanyl