title: Morphine exposure during early life alters thermal and mechanical thresholds in rats.
abstract: BACKGROUND
  Morphine is an opioid analgesic used to relieve moderate-to-severe pain, including pain in neonates at the intensive care unit. In our previous study, we showed that repeated morphine exposure during early life could trigger long-lasting implications on the developing nervous system, such as long-term neurochemical and behavioral alterations in adult rats.
  
  
  OBJECTIVE
  The aim of our study was to determine the short-, intermediate-, and long-term effects of repeated morphine administration during early life on the thermal and mechanical thresholds and on the central levels (cerebral cortex and brainstem) of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and cytokines (interleukin-6 [IL-6] and IL-10).
  
  
  METHODS
  Male Wistar rats were administered morphine (5μg/day, s.c.) or saline for 7days from postnatal day 8 (P8) until P14. The nociceptive effect was assessed by evaluating the thermal response using the hot plate test (HPT) and the mechanical response by Von Frey (VFT) and Randall-Selitto (RST) tests at P16, P30, and P60. BDNF, NGF, IL-6, and IL-10 levels were measured in the cerebral cortex and brainstem.
  
  
  RESULTS
  In HPT, no difference in latency was observed at P16; however, at P30 and P60, the morphine-treated group exhibited a less increase in the nociceptive threshold compared to the saline group. VFT and RST demonstrated an interaction between group and age, where the morphine group showed a less pronounced increase in latency with age, which is indicative of allodynia. In the cerebral cortex, an association between BDNF and NGF levels and age was observed, where neurotrophin level increased with age in the saline group, and decreased with age in the morphine group. In addition, IL-10 levels decreased with age in both groups; however, there was no significant difference in IL-6 levels. In the brainstem, BDNF, NGF, IL-6, and IL-10 levels increased with age.
  
  
  CONCLUSIONS
  Repeated morphine exposure during neonatal life triggered alterations in the nociceptive behavior, including thermal hyperalgesia and mechanical allodynia, as well as decreased levels of BDNF and NGF in the cerebral cortex. Our study highlights the importance of extensive comprehension of the pharmacological interventions during CNS maturation.
authors.affiliation: Pharmacology of Pain and Neuromodulation Laboratory: Preclinical Researches, Department of Pharmacology, Institute of Basic Health Sciences (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 90050-170, Brazil; Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-003, Brazil; Graduate Program in Biological Sciences: Physiology, ICBS, UFRGS, Porto Alegre, RS 90050-170, Brazil.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nunes
authors.affiliation: Pharmacology of Pain and Neuromodulation Laboratory: Preclinical Researches, Department of Pharmacology, Institute of Basic Health Sciences (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 90050-170, Brazil; Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-003, Brazil.
authors.forename: Liciane Fernandes
authors.initials: LF
authors.lastname: Medeiros
authors.affiliation: Pharmacology of Pain and Neuromodulation Laboratory: Preclinical Researches, Department of Pharmacology, Institute of Basic Health Sciences (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 90050-170, Brazil; Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-003, Brazil; Graduate Program in Biological Sciences: Pharmacology and Therapeutics, ICBS, UFRGS, Porto Alegre, 90050-170, Brazil.
authors.forename: Joice Soares
authors.initials: JS
authors.lastname: de Freitas
authors.affiliation: Pharmacology of Pain and Neuromodulation Laboratory: Preclinical Researches, Department of Pharmacology, Institute of Basic Health Sciences (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 90050-170, Brazil; Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-003, Brazil; Graduate Program in Biological Sciences: Physiology, ICBS, UFRGS, Porto Alegre, RS 90050-170, Brazil.
authors.forename: Isabel Cristina
authors.initials: IC
authors.lastname: Macedo
authors.affiliation: Pharmacology of Pain and Neuromodulation Laboratory: Preclinical Researches, Department of Pharmacology, Institute of Basic Health Sciences (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 90050-170, Brazil; Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-003, Brazil.
authors.forename: Jonnsin
authors.initials: J
authors.lastname: Kuo
authors.affiliation: Postgraduate Program in Health and Human Development, Unilasalle University Centre, Canoas, RS, 92010-000, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: de Souza
authors.affiliation: Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-003, Brazil.
authors.forename: Joanna Rippol
authors.initials: JR
authors.lastname: Rozisky
authors.affiliation: Graduate Program in Biological Sciences: Pharmacology and Therapeutics, ICBS, UFRGS, Porto Alegre, 90050-170, Brazil.
authors.forename: Wolnei
authors.initials: W
authors.lastname: Caumo
authors.affiliation: Pharmacology of Pain and Neuromodulation Laboratory: Preclinical Researches, Department of Pharmacology, Institute of Basic Health Sciences (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 90050-170, Brazil; Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-003, Brazil; Graduate Program in Biological Sciences: Physiology, ICBS, UFRGS, Porto Alegre, RS 90050-170, Brazil. Electronic address: iltorres@hcpa.edu.br.
authors.forename: Iraci L S
authors.initials: ILS
authors.lastname: Torres
mesh_terms: D000375:Aging / Q000502:physiology*; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009414:Nerve Growth Factors / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012684:Sensory Thresholds / Q000187:drug effects* / Q000502:physiology; D013696:Temperature; D014110:Touch
chemical_list: D000701:Analgesics, Opioid; D009414:Nerve Growth Factors; D009020:Morphine
keywords: BDNF; Cytokines; Morphine; NGF; Neonate rats; Nociception