Tolerance, opioid-induced allodynia and withdrawal associated allodynia in infant and young rats

doi:10.1016/j.neuroscience.2006.08.078

Neuroscience

Volume 144, Issue 1, 5 January 2007, Pages 247-262

https://doi.org/10.1016/j.neuroscience.2006.08.078 Get rights and content

Abstract

Our laboratory has previously characterized age-dependent changes in nociception upon acute morphine withdrawal. This study characterizes changes in mechanical and thermal nociception following acute, intermittent, or continuous morphine administration in infant (postnatal days 5–8) and young (postnatal days 19–21) rats. Morphine was given as a single acute administration (AM), intermittently twice a day for 3 days (IM), or continuously for 72 h via pump (CM). AM did not produce long-term changes in mechanical or thermal nociception in either infant or young rats. CM produced changes in mechanical nociception that included the development of tolerance, opioid-induced mechanical allodynia and withdrawal-associated mechanical allodynia in young rats, but only tolerance and a prolonged withdrawal-associated mechanical allodynia in infant rats. IM produced withdrawal-associated mechanical allodynia in both infant and young rats. Measuring paw withdrawal responses to thermal stimuli, infant and young rats showed tolerance without opioid-induced thermal hyperalgesia or withdrawal-associated thermal hyperalgesia following CM. In contrast to CM, withdrawal-associated thermal hyperalgesia was seen in both ages following IM. In conclusion, CM versus IM differentially modified mechanical and thermal nociception, suggesting that opioid-dependent thermal hyperalgesia and mechanical allodynia can be dissociated from each other in infant and young rats. Furthermore, tolerance, opioid-induced hypersensitivity, and withdrawal-associated hypersensitivity are age-specific and may be mediated by distinct mechanisms.

Section snippets

Animals

P5–12 (infant) and P18–24 (young) Sprague–Dawley rats (Charles River Laboratories, Raleigh, NC, USA) of both sexes were housed in litters culled at 10 pups/dam in a 12-h light/dark cycle (lights on at 7 a.m.) with food and water available ad libitum. All experimental protocols were approved by the Institutional Animal Care and Use Committees at Stanford University and the University of South Carolina. All experiments conformed to the guidelines of the Committee for Research and Ethical issues

Weight gain: infant rats

Both CM and IM dose-dependently reduced animal weight compared with saline control animals (Table 1). A difference in weight at any one point may be attributed to 1) loss of body weight or 2) decrease in normal weight gain. Normal weight gain during this period of development is approximately 2 g/day. A decrease in weight gain was observed on experimental days 3 and 4 in rats intermittently administered 0.5 and 1 mg/kg morphine, respectively, as compared with saline controls. Reduced weight

Discussion

AM, IM, and CM opioid administration is used clinically in infants and children (Lynn et al., 2000). The current study shows both modality specific and age-specific alterations in nociception following different morphine schedules. A single AM administration decreased mechanical thresholds at 24 h in P7, but not P21 rats. In addition, mechanical and thermal nociception was altered in an age-dependent manner following 72 h of IM or CM (Table 5). Withdrawal-associated mechanical allodynia was

Conclusions

In summary we have shown that morphine-induced changes in nociception are dependent upon 1) the developmental window in which exposure occurs and 2) the dosing schedule. IM may lead to sensitization while CM may preferentially produce tolerance. In a study comparing i.v. IM versus CM more post-operative infants had pain scores indicating distress in the intermittent versus continuous exposure group (Lynn et al., 2000). Thus, in the clinic increased opiate doses may be required to alleviate pain

Acknowledgments

Supported by United States National Institutes of Health grants NS13108 (J.J.K.), NS4472901 (S.M.S.), and the Alejandro and Lida Zaffaroni Innovation Fund for Addiction Research (S.M.S.).

References (82)

D. Alvares et al.
Building blocks of pain: the regulation of key molecules in spinal sensory neurones during development and following peripheral axotomy
Pain Suppl
(1999)
K.J. Anand et al.
Long-term behavioral effects of repetitive pain in neonatal rat pups
Physiol Behav
(1999)
J.L. Azorlosa
The effect of chronic naltrexone pretreatment on associative vs. non-associative morphine tolerance
Drug Alcohol Depend
(1994)
G. Barr et al.
Neonatal withdrawal following pre- and postnatal exposure to methadone in the rat
Pharmacol Biochem Behav
(1998)
A.I. Basbaum
Insights into the development of opioid tolerance
Pain
(1995)
B. Beland et al.
Mu- and delta-opioid receptors are downregulated in the largest diameter primary sensory neurons during postnatal development in rats
Pain
(2001)
E. Celerier et al.
Evidence for opiate-activated NMDA processes masking opiate analgesia in rats
Brain Res
(1999)
F. Champagne et al.
Like mother, like daughter: evidence for non-genomic transmission of parental behavior and stress responsivity
Prog Brain Res
(2001)
M.A. Compton
Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status
J Pain Symptom Manage
(1994)
P. Compton et al.
Pain responses in methadone-maintained opioid abusers
J Pain Symptom Manage
(2000)

P. Compton et al.

Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent

Drug Alcohol Depend

(2001)

S.M. Crain et al.

Chronic morphine-treated sensory ganglion neurons remain supersensitive to the excitatory effects of naloxone for months after return to normal culture medium: an in vitro model of ‘protracted opioid dependence.’

Brain Res

(1995)

M. Doverty et al.

Hyperalgesic responses in methadone maintenance patients

Pain

(2001)

S.A. Dunbar et al.

Periodic abstinence enhances nociception without significantly altering the antinociceptive efficacy of spinal morphine in the rat

Neurosci Lett

(2003)

A.S. Fleming et al.

Neurobiology of mother-infant interactions: experience and central nervous system plasticity across development and generations

Neurosci Biobehav Rev

(1999)

L.H. Gold et al.

Prolonged tolerance, dependence and abstinence following subcutaneous morphine pellet implantation in the rat

Eur J Pharmacol

(1994)

D.H. Kim et al.

Morphine analgesia and acute physical dependence: rapid onset of two opposing, dose-related processes

Brain Res

(1990)

J.P. Laulin et al.

Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity

Neuroscience

(1999)

A.M. Lynn et al.

Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions

Pain

(2000)

J. Mao

Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy

Pain

(2002)

R. Nandi et al.

The functional expression of mu opioid receptors on sensory neurons is developmentally regulated: morphine analgesia is less selective in the neonate

Pain

(2004)

W. Rahman et al.

Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia

Brain Res Dev Brain Res

(1998)

W. Rahman et al.

Development of spinal opioid systems

Reg Anesth Pain Med

(1999)

S.E. Rapp et al.

Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review

Pain

(1995)

J. Schouenborg

Learning in sensorimotor circuits

Curr Opin Neurobiol

(2004)

G. Schulteis et al.

Repeated experience with naloxone facilitates acute morphine withdrawal: potential role for conditioning processes in acute opioid dependence

Pharmacol Biochem Behav

(2003)

S. Sweitzer et al.

Exaggerated nociceptive responses on morphine withdrawal: roles of protein kinase C epsilon and gamma

Pain

(2004)

S.M. Sweitzer et al.

Mechanical allodynia and thermal hyperalgesia upon acute opioid withdrawal in the neonatal rat

Pain

(2004)

A. Taddio et al.

Effect of neonatal circumcision on pain response during subsequent routine vaccination

Lancet

(1997)

S.R. Thornton et al.

Fentanyl self-administration in juvenile rats that were tolerant and dependent to fentanyl as infants

Pharmacol Biochem Behav

(2000)

S.R. Thornton et al.

Long-term alterations in opiate antinociception resulting from infant fentanyl tolerance and dependence

Eur J Pharmacol

(1998)

S.R. Thornton et al.

Characterization of neonatal rat morphine tolerance and dependence

Eur J Pharmacol

(1997)

M. van Dijk et al.

Efficacy of continuous versus intermittent morphine administration after major surgery in 0-3-year-old infants; a double-blind randomized controlled trial

Pain

(2002)

T.W. Vanderah et al.

Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin

Pain

(2001)

S.M. Walker et al.

Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn

Pain

(2003)

J.H. Arnold et al.

Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation

Anesthesiology

(1990)

G.A. Barr

Behavioral effects of opiates during development

S. Barron et al.

Pup-induced maternal behavior in adult and juvenile rats exposed to alcohol prenatally

Alcohol Clin Exp Res

(1985)

J.B. Bederson et al.

Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla

Somatosens Mot Res

(1990)

S. Beggs et al.

The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activity-dependent process

Eur J Neurosci

(2002)

N.W. Bond et al.

Prenatal alcohol consumption and open-field behaviour in rats: effects of age at time of testing

Psychopharmacology (Berl)

(1977)

Cited by (31)

Interaction between buprenorphine and norbuprenorphine in neonatal opioid withdrawal syndrome
2023, Drug and Alcohol Dependence
Buprenorphine (BUP) is the preferred treatment for opioid use disorder during pregnancy but can cause neonatal opioid withdrawal syndrome (NOWS). Norbuprenorphine (NorBUP), an active metabolite of BUP, is implicated in BUP-associated NOWS. We hypothesized that BUP, a low-efficacy agonist of mu opioid receptors, will not antagonize NorBUP, a high-efficacy agonist of mu opioid receptors, in producing NOWS. To test this hypothesis, we treated pregnant Long-Evans rats with BUP (0, 0.01, 0.1 or 1 mg/kg/day) ± NorBUP (1 mg/kg/day) from gestation day 9 until pup delivery, and tested pups for opioid dependence using our established NOWS model. We used LC-MS-MS to quantify brain concentrations of BUP, NorBUP, and their glucuronide conjugates. BUP had little effect on NorBUP-induced NOWS, with the exception of 1 mg/kg/day BUP significantly increasing NorBUP-induced NOWS by 58% in females. BUP and NorBUP brain concentrations predicted NOWS in multiple linear regression models. Interestingly, NorBUP contributed more to NOWS in females (β_NorBUP = 51.34, p = 0.0001) than in males (β_NorBUP = 19.21, P = 0.093), while BUP was similar for females (β_BUP = 10.62, P = 0.0017) and males (β_BUP = 11.38, P = 0.009). We are the first to report that NorBUP induces NOWS in the presence of BUP and it is more influential in females than males in the contribution of NorBUP to BUP-associated NOWS. These findings suggest that females are more susceptible to NorBUP-induced NOWS, and that treatment strategies that reduce prenatal NorBUP exposure may be more effective for females than males.
Buprenorphine reduces somatic withdrawal in a mouse model of early-life morphine exposure
2023, Drug and Alcohol Dependence
The rising prevalence of early-life opioid exposure has become a pressing public health issue in the U.S. Neonates exposed to opioids in utero are at risk of experiencing a constellation of postpartum withdrawal symptoms commonly referred to as neonatal opioid withdrawal syndrome (NOWS). Buprenorphine (BPN), a partial agonist at the mu-opioid receptor (MOR) and antagonist at the kappa-opioid receptor (KOR), is currently approved to treat opioid use disorder in adult populations. Recent research suggests that BPN may also be effective in reducing withdrawal symptoms in neonates who were exposed to opioids in utero. We sought to determine whether BPN attenuates somatic withdrawal in a mouse model of NOWS. Our findings indicate that the administration of morphine (10 mg/kg, s.c.) from postnatal day (PND) 1–14 results in increased somatic symptoms upon naloxone-precipitated (1 mg/kg, s.c.) withdrawal. Co-administration of BPN (0.3 mg/kg, s.c.) from PND 12–14 attenuated symptoms in morphine-treated mice. On PND 15, 24 h following naloxone-precipitated withdrawal, a subset of mice was examined for thermal sensitivity in the hot plate test. BPN treatment significantly increased response latency in morphine-exposed mice. Lastly, neonatal morphine exposure elevated mRNA expression of KOR, and reduced mRNA expression of corticotropin-releasing hormone (CRH) in the periaqueductal gray when measured on PND 14. Altogether, this data provides support for the therapeutic effects of acute low-dose buprenorphine treatment in a mouse model of neonatal opioid exposure and withdrawal.
Divergent profiles of fentanyl withdrawal and associated pain in mice and rats
2021, Pharmacology Biochemistry and Behavior
Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species' strengths as model systems and can inform experimental design in studies of opioid withdrawal.
Painful to describe, painful to diagnose: Opioid-induced hyperalgesia
2015, British Journal of Anaesthesia
Morphine exposure in early life increases nociceptive behavior in a rat formalin tonic pain model in adult life
2011, Brain Research
Citation Excerpt :
Thus, the increase in formalin-induced nociceptive behavior observed in this study suggests a central hyperexcitability of the ascending second-order dorsal horn neurons induced by previous sustained exposure to morphine, and this is a long-term effect. Our results agree with those of Zissen et al. (2006, 2007), who have demonstrated that while infant rats (P5 to P8) are more sensitive to the long-term changes in formalin-induced pain and mechanical thresholds following continuous exposure to morphine, when compared to young rats (P19 to P21), they are also better able to compensate for changes in mechanical thresholds following intermittent administration of morphine, given twice a day for 3 days. It is possible that short bouts of morphine withdrawal-induced excitation may off-set morphine-induced inhibition in infants, but not in young rats, and thus, may better maintain the balance of activity and inactivity during this crucial developmental phase.
Considering the importance of a deeper understanding of the effect throughout life of opioid analgesia at birth, our objective was to determine whether morphine administration in early life, once a day for 7 days in 8-day-old rats, alters the nociceptive response over the short (P16), medium (P30), and long term (P60) and to evaluate which system is involved in the altered nociceptive response. The nociceptive responses were assessed by the formalin test, and the behavior analyzed was the total time spent in biting and flicking of the formalin-injected hindpaw, recorded during the first 5 min (phase I) and from 15–30 min (phase II). The morphine group showed no change in nociceptive response at P16, but at P30 and P60, the nociceptive response was increased in phase I, and in both phases, respectively. At P30 and P60, the animals received a non-steroidal anti-inflammatory drug (indomethacin) or NMDA receptor antagonist (ketamine) 30 min before the formalin test. The increase in the nociceptive response was completely reversed by ketamine, and partially by indomethacin. These results indicate that early morphine exposure causes an increase in the nociceptive response in adult life. It is possible that this lower nociception threshold is due to neuroadaptations in nociceptive circuits, such as the glutamatergic system. Thus, this work demonstrates the importance of evaluating clinical consequences related to early opioid administration and suggests a need for a novel design of agents that may counteract opiate-induced neuroplastic changes.
Perioperative management of the opioid-tolerant patient
2009, Advances in Anesthesia
Citation Excerpt :
A recent study by Zissen and colleagues [27] further attempted to characterize whether the dosing schedule and the development of OIH is dependent on rat developmental age. Zissen and colleagues [27] report that thermal hyperalgesia and mechanical hyperalgesia were observed only in young rats exposed to intermittent and continuous dosing, respectively, and postulate that age of exposure and drug schedule are important factors in the development of hyperalgesia. These apparent changes in pain sensitization may also last well beyond the period of exposure and recovery.

View all citing articles on Scopus

View full text

Pain mechanismTolerance, opioid-induced allodynia and withdrawal associated allodynia in infant and young rats

Abstract

Section snippets

Animals

Weight gain: infant rats

Discussion

Conclusions

Acknowledgments

Pain Suppl

Physiol Behav

Drug Alcohol Depend

Pharmacol Biochem Behav

Pain

Pain

Brain Res

Prog Brain Res

J Pain Symptom Manage

J Pain Symptom Manage

Drug Alcohol Depend

Brain Res

Pain

Neurosci Lett

Neurosci Biobehav Rev

Eur J Pharmacol

Brain Res

Neuroscience

Pain

Pain

Pain

Brain Res Dev Brain Res

Reg Anesth Pain Med

Pain

Curr Opin Neurobiol

Pharmacol Biochem Behav

Pain

Pain

Lancet

Pharmacol Biochem Behav

Eur J Pharmacol

Eur J Pharmacol

Pain

Pain

Pain

Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation

Anesthesiology

Behavioral effects of opiates during development

Pup-induced maternal behavior in adult and juvenile rats exposed to alcohol prenatally

Alcohol Clin Exp Res

Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla

Somatosens Mot Res

The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activity-dependent process

Eur J Neurosci

Prenatal alcohol consumption and open-field behaviour in rats: effects of age at time of testing

Psychopharmacology (Berl)

Pain mechanism
Tolerance, opioid-induced allodynia and withdrawal associated allodynia in infant and young rats