André Laferrière

Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates.

Background: Postsurgical administration of opiates in patients with obstructive sleep apnea (OSA) has recently been linked to an increased risk for respiratory complications. The authors have attributed this association to an effect of recurrent oxygen desaturation accompanying OSA on endogenous opioid mechanisms that, in turn, alter responsiveness to subsequent administration of exogenous opiates. In a retrospective study, the authors have shown that oxygen desaturation and young age in children with OSA are correlated with a reduced opiate requirement for postoperative analgesia. Methods: The current study was designed to test that conclusion prospectively in 22 children with OSA scheduled to undergo adenotonsillectomy. The children were stratified to those having displayed < 85% or ≥ 85% oxygen saturation nadir during sleep preoperatively. Using a blinded design, the children were given morphine postoperatively to achieve an identical behavioral pain score. Results: As compared with children in the ≥ 85% group, the < 85% oxygen saturation nadir group required one half the total analgesic morphine dose postoperatively, indicating heightened analgesic sensitivity to morphine after recurrent hypoxemia. Conclusions: Previous recurrent hypoxemia in OSA is associated with increased analgesic sensitivity to subsequent morphine administration. Therefore, opiate dosing in children with OSA must take into account a history of recurrent hypoxemia.

Evidence that pregabalin reduces neuropathic pain by inhibiting the spinal release of glutamate

J. Neurochem. (2010) 113, 552–561.

Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia.

BackgroundObstructive sleep apnea (OSA) in children is often associated with recurrent hypoxemia during sleep. In developing animals, central opioid neuropeptide content is high, and opioid receptors are up-regulated after recurrent hypoxia. The authors hypothesized that children with recurrent hypoxemia due to OSA might have altered central opioid functionality that could affect their responsiveness to opioid drugs. Using a retrospective database, we assessed the relation of age and preoperative oxygen saturation to the cumulative postoperative morphine dose administered for analgesia in children with OSA undergoing adenotonsillectomy. MethodsInclusion criteria were (1) adenotonsillectomy for OSA; (2) no concomitant pathology; (3) intraoperative administration of short-acting opioid drugs; (4) endotracheal extubation on awakening in the operating room; and (5) morphine as the parenteral, postoperative analgesic. ResultsForty-six children (16 girls) fulfilled the inclusion criteria. Age and preoperative arterial oxygen saturation (Sao2) nadir, either individually (P = 0.023, P = 0.0003, respectively) or in combination (P = 0.00009), exhibited a significant correlation to the morphine dose required for analgesia. Four of these children, aged 26.5 ± 13.2 months, with a preoperative Sao2 nadir of 70.3 ± 12.9%, did not require any postoperative morphine for analgesia at all. ConclusionsThe authors speculate that the reduced morphine requirement for analgesia in children displaying oxygen desaturation associated with severe OSA may be related to their young age and to an up-regulation of central opioid receptors consequent to recurrent hypoxemia. In evaluating OSA in children, preoperative determination of the Sao2 nadir is important for predicting the postoperative opioid dosage required for analgesia.

Cutaneous tactile allodynia associated with microvascular dysfunction in muscle

BackgroundCutaneous tactile allodynia, or painful hypersensitivity to mechanical stimulation of the skin, is typically associated with neuropathic pain, although also present in chronic pain patients who do not have evidence of nerve injury. We examine whether deep tissue microvascular dysfunction, a feature common in chronic non-neuropathic pain, contributes to allodynia.ResultsPersistent cutaneous allodynia is produced in rats following a hind paw ischemia-reperfusion injury that induces microvascular dysfunction, including arterial vasospasms and capillary slow flow/no-reflow, in muscle. Microvascular dysfunction leads to persistent muscle ischemia, a reduction of intraepidermal nerve fibers, and allodynia correlated with muscle ischemia, but not with skin nerve loss. The affected hind paw muscle shows lipid peroxidation, an upregulation of nuclear factor kappa B, and enhanced pro-inflammatory cytokines, while allodynia is relieved by agents that inhibit these alterations. Allodynia is increased, along with hind paw muscle lactate, when these rats exercise, and is reduced by an acid sensing ion channel antagonist.ConclusionOur results demonstrate how microvascular dysfunction and ischemia in muscle can play a critical role in the development of cutaneous allodynia, and encourage the study of how these mechanisms contribute to chronic pain. We anticipate that focus on the pain mechanisms associated with microvascular dysfunction in muscle will provide new effective treatments for chronic pain patients with cutaneous tactile allodynia.

Recurrent hypoxia in rats during development increases subsequent respiratory sensitivity to fentanyl.

Background: In children with a history of significant obstructive sleep apnea who undergo adenotonsillectomy, postsurgical administration of opiates has been alleged to be associated with an increased risk for respiratory complications, including respiratory depression. The authors hypothesize that this association is due to an effect of recurrent hypoxemia that accompanies more severe obstructive sleep apnea on altered responsiveness to subsequent exogenous opiates. Methods: The current study was designed to test the effect of recurrent hypoxia in the developing rat on respiratory responses to subsequent administration of the μ-opioid agonist fentanyl. Rats were exposed to 12% oxygen balance nitrogen for 7 h daily for 17 days, from postnatal day 17 to 33, a period equivalent to human childhood. After 17 additional days in room air, rats were given a fentanyl dose and tested for their respiratory response to fentanyl using a whole body plethysmograph. Rats undergoing similar protocols without recurrent hypoxia served as controls. Results: As compared with controls, rats preexposed to recurrent hypoxia displayed a more profound depression with fentanyl in minute ventilation, respiratory frequency, tidal volume, and tidal volume divided by inspiratory time that represents respiratory drive. These results indicated an increased respiratory sensitivity to fentanyl after recurrent hypoxia. Conclusions: Previous recurrent hypoxia increases respiratory sensitivity to subsequent opiate agonists. If these findings are applicable to humans, opiate dosing in children must be adjusted depending on history of recurrent hypoxemia to avoid respiratory depression.

Role of NFκB in an animal model of complex regional pain syndrome - type I (CRPS-I)

UNLABELLED NFkappaB is involved in several pathogenic mechanisms that are believed to underlie the complex regional pain syndrome (CRPS), including ischemia, inflammation and sensitization. Chronic postischemia pain (CPIP) has been developed as an animal model that mimics the symptoms of CRPS-I. The possible involvement of NFkappaB in CRPS-I was studied using CPIP rats. Under sodium pentobarbital anesthesia, a tourniquet was placed around the rat left ankle joint, producing 3 hours of ischemia, followed by rapid reperfusion (IR injury). NFkappaB was measured in nuclear extracts of muscle and spinal cord tissue using ELISA. Moreover, the anti-allodynic (mechanical and cold) effect was tested for systemic, intrathecal, or intraplantar treatment with the NFkappaB inhibitor pyrrolidine dithiocarbamate (PDTC). At 2 and 48 hours after IR injury, NFkappaB was elevated in muscle and spinal cord of CPIP rats compared to shams. At 7 days, NFkappaB levels were normalized in muscle, but still elevated in spinal cord tissue. Systemic PDTC treatment relieved mechanical and cold allodynia in a dose-dependent manner, lasting for at least 3 hours. Intrathecal-but not intraplantar-administration also relieved mechanical allodynia. The results suggest that muscle and spinal NFkappaB plays a role in the pathogenesis of CPIP and potentially of human CRPS. PERSPECTIVE Using the CPIP model, we demonstrate that NFkappaB is involved in the development of allodynia after a physical injury (ischemia and reperfusion) without direct nerve trauma. Since CPIP animals exhibit many features of human CRPS-I, this observation indicates a potential role for NFkappaB in human CRPS.

PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain

BackgroundChronic pain occurs when normally protective acute pain becomes pathologically persistent. We examined here whether an isoform of protein kinase C (PKC), PKMζ, that underlies long-term memory storage in various brain regions, also sustains nociceptive plasticity in spinal cord dorsal horn (SCDH) mediating persistent pain.ResultsCutaneous injury or spinal stimulation produced persistent increases of PKMζ, but not other atypical PKCs in SCDH. Inhibiting spinal PKMζ, but not full-length PKCs, reversed plasticity-dependent persistent painful responses to hind paw formalin and secondary mechanical hypersensitivity and SCDH neuron sensitization after hind paw capsaicin, without affecting peripheral sensitization-dependent primary heat hypersensitivity after hind paw capsaicin. Inhibiting spinal PKMζ, but not full-length PKCs, also reversed mechanical hypersensitivity in the rat hind paw induced by spinal stimulation with intrathecal dihydroxyphenylglycine. Spinal PKMζ inhibition also alleviated allodynia 3 weeks after ischemic injury in rats with chronic post-ischemia pain (CPIP), at a point when allodynia depends on spinal changes. In contrast, spinal PKMζ inhibition did not affect allodynia in rats with chronic contriction injury (CCI) of the sciatic nerve, or CPIP rats early after ischemic injury, when allodynia depends on ongoing peripheral inputs.ConclusionsThese results suggest spinal PKMζ is essential for the maintenance of persistent pain by sustaining spinal nociceptive plasticity.

Plasticity of the medial prefrontal cortex: Facilitated acquisition of intracranial self-stimulation by pretraining stimulation

Prior electrical stimulation of the medial prefrontal cortex MFC facilitated the subsequent acquisition of intracranial self-stimulation (ICSS) from the same MFC electrode site. Stimulations that were spaced over a period of six days were more effective in producing this facilitation than the same number of stimulations delivered over a two day period. These data suggest that the rewarding effects of MFC stimulation may involve some process akin to the kindling phenomenon and as such may provide insights in the neuronal modifications thought to underlie learning and memory.

Amphetamine and increases in current intensity modulate reward in the hypothalamus and substantia nigra but not in the prefrontal cortex

Abstract Amphetamine and increased stimulation current facilitated responding for variable interval scheduled brain stimulation of the lateral hypothalamus (LH) and substantia nigra (SN) while medial prefrontal cortex (PFC) self-stimulation was not increased. This suggests that these treatments increase the rewarding effect of brain stimulation in the LH and SN but not PFC. In confirmation, using a Findley concurrent schedule, it was shown that increasing hypothalamic stimulation current increases the rats preference for LH over PFC stimulation, but increasing cortical stimulation intensity does not alter the preference for PFC relative to LH stimulation. It is concluded that there are differences in the neural substrates of reward produced by stimulation of the PFC and LH and SN.

Elimination of medial prefrontal cortex self-stimulation following transection of efferents to the sulcal cortex in the rat

Intracranial self-stimulation (ICSS) of the medial prefrontal cortex (MFC) was not affected by lesions of the medial forebrain bundle, the nucleus accumbens or medialis dorsalis. However, bilateral, parasagittal knife cuts that transected fibers interconnecting the medial and sulcal cortices eliminated ICSS from the MFC with no apparent recovery over a 21 day test period. Similar knife cuts produced only transient effects on lateral hypothalamic ICSS. These data suggest that the neural substrates of frontal cortex ICSS are very different than those that subserve ICSS along the medial forebrain bundle.