title: Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats.
abstract: OBJECTIVE
  Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substanceP(SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action.
  
  
  METHODS
  Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry.
  
  
  RESULTS
  Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1-4). Expression of SP was increased in the morphine + fosaprepitant group.
  
  
  CONCLUSIONS
  The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals.
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Pranav
authors.initials: P
authors.lastname: Prasoon
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Shivani
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Mayank
authors.initials: M
authors.lastname: Gautam
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Saroj
authors.initials: S
authors.lastname: Kaler
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Subrata Basu
authors.initials: SB
authors.lastname: Ray
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D059390:Breakthrough Pain / Q000188:drug therapy / Q000378:metabolism; D004357:Drug Synergism; D004361:Drug Tolerance; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P; C579707:fosaprepitant; D009020:Morphine
keywords: Breakthrough pain; morphine tolerance; nociception; rodent; thermal escape behavior; withdrawal threshold