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

Abstract

Upon withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. We present evidence that neonatal rats exhibit allodynia and hyperalgesia on acute opiate withdrawal. Postnatal 7 and 21 day rats were used to approximately model a full term human infant and a human child, respectively. The opiate antagonist naloxone was used to precipitate withdrawal at 30 or 120 min after a single acute administration of morphine. Alternatively, rats were allowed to undergo spontaneous withdrawal. Behavioral manifestations of withdrawal syndrome were not observed when naloxone was administered at 30 min post-morphine, but were present when withdrawal was precipitated at 120 min. Spontaneous and precipitated withdrawal from a single acute administration of morphine produced mechanical allodynia and thermal hyperalgesia in postnatal day 7 rats and mechanical allodynia in postnatal day 21 rats. A higher dose of morphine was required to produce mechanical allodynia in postnatal day 21 versus 7 rats but this increase was independent of the analgesic efficacy of morphine at these two ages. The present work illustrates the need to examine the phenomenon of hypersensitivity upon opioid withdrawal in the human pediatric population.

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

“…We have previously reported an early and transient decrease in mechanical thresholds at 4-5 hours after 1, but not, 0.5 mg/kg AM (Sweitzer et al, 2004b). Similar to previous findings that mechanical threshold returned to baseline levels by 6 hours post-morphine (Sweitzer et al, 2004b), in the present study 0.5 and 1 mg/kg morphine have no effect on mechanical thresholds at 24 hours (experimental day 2). In contrast, a decrease in mechanical threshold was observed at 24 hours (experimental day 2) following 6 mg/kg AM (Figure 2A).…”

“…We have previously reported an early and transient decrease in mechanical thresholds at 3-5 hours after 1, or 3 mg/kg AM (Sweitzer et al, 2004b). In contrast to the mechanical allodynia present at 24 hours in infant rats, long term changes in mechanical threshold were not observed following AM in the young rats ( Figure 2B).…”

“…In previous studies we reported an in vitro and in vivo model of age-specific acute morphine withdrawal-associated hypersensitivity (Sweitzer et al, 2004a, Sweitzer et al, 2004b. The present study addressed the effect of acute, continuous, and intermittent morphine administration on mechanical thresholds and thermal latencies in P5-7 (infant) and P18-21 (young) rats that approximately correspond in neurological developmental to newborn human infants and young children (Dobbing, 1981).…”

“…Currently, human infants are routinely treated with opioids for pain relief and for the purposes of sedation to permit mechanical ventilation (van Dijk et al, 2002, Simons et al, 2003. With the observation of neonatal abstinence syndrome in 48-84% of infants administered intravenous opioids (Norton, 1988, Arnold et al, 1990, French and Nocera, 1994, Franck and Vilardi, 1995, Franck et al, 1998 it is imperative to assess whether tolerance, opioid-induced pain, and withdrawal pain are present in the pediatric population and whether opioid exposure alters normal synaptic development and produces long-term somatosensory changes Smith, 1998, Thornton et al, 2000).In previous studies we reported an in vitro and in vivo model of age-specific acute morphine withdrawal-associated hypersensitivity (Sweitzer et al, 2004a, Sweitzer et al, 2004b. The present study addressed the effect of acute, continuous, and intermittent morphine administration on mechanical thresholds and thermal latencies in P5-7 (infant) and P18-21 (young) rats that approximately correspond in neurological developmental to newborn human infants and young children (Dobbing, 1981).…”

Protein kinase C in pain: Involvement of multiple isoforms

“…In afferent neurons, PKC activation alone increases substance P and CGRP release as well as potentiates potassium-and capsaicin-stimulated release of these neuropeptides (49)(50)(51). More specifically, inhibition of PKCε decreases capsaicin-induced release of glutamate and CGRP in isolated spinal cords (52). In addition to topical capsaicin, chemokines stimulate the release of CGRP from afferent neurons in a PKC dependent manner (53).…”