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.The current study was designed to test the effect of recurrent hypoxia in the developing rat on respiratory responses to subsequent administration of the mu-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.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.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.
Several key events in the development of the perinatal rat phrenic nerve and diaphragm have been determined, including the following: i) Fetal inspiratory motor discharge commences within the phrenic motoneuron (PMN) pool on embryonic day (E)17; gestation period is 21 days.ii) Phrenic axons grow to innervate the full extent of diaphragmatic musculature by E17-E18.iii) There is a radical maturation of PMN morphology during the period from E16-E20.We have subsequently gone on to examine functional changes by examining PMN electrophysiological and diaphragm contractile properties prior and subsequent to these pivotal developmental stages (E16-P0).Summary data will be presented demonstrating the following: 1) As PMNs develop from E16 to P0, there are changes in passive membrane properties; resting membrane potential becomes hyperpolarized by ~10 mV, the input resistance decreases ~3-fold, and the mean rheobase increases by a factor of ~2.6.2) There are significant changes in the amplitude, duration and the afterpotentials of action potentials from E16-P0 which places restrictions on the repetitive firing patterns of fetal PMNs.3) The changes in PMN firing properties are primarily due to age-dependent changes in the expression of voltage-sensitive calcium and calcium-activated potassium currents.4) Both dye and electrical coupling have been detected amongst subpopulations of PMNs between ages E16 and P0. 5) There are marked changes in diaphragm muscle contractile properties that develop in concert with PMN repetitive firing properties so that the full-range of diaphragm force recruitment can be utilized at each age and potential problems of diaphragm fatigue are minimized.Data presented will be derived from the following references: commentary review reports meeting abstracts primary research S3 lowed by 21% O 2 -79% N 2 for 5 min, either on 6 consecutive days (recurrent episodic hypoxia), or on the 6th day only, following 5 daily normoxic exposures (single episodic hypoxia).Brains were collected either 5 min or 2 h after the last gaseous exposure.Brainstem sections underwent autoradiography with iodinated substance P for NK-1R or DAMGO for MOR.In nucleus tractus solitarius (NTS) from brains collected 2 h after the last exposure, the binding densities of NK-1R and MOR were unaltered by a single episodic hypoxia, and were greatly increased after recurrent episodic hypoxia, indicating an upregulation of both receptors by the recurrent episodic stimulus.In the NTS from the brains collected 5 min after the last hypoxic exposure, there was an important discrepancy in the binding response between the NK-1R and the MOR: The NK-1R displayed a significant decrease in ligand binding after both single and recurrent episodic hypoxia, implying enhanced receptor internalization.In contrast, the binding of MOR was not changed, implying that the rate of receptor internalization was not altered by the hypoxic exposure.This difference would result in relatively greater availability of functional MOR to opioid peptides during hypoxia.At present, we are carrying out the same experiments in developing piglets, using the same hypoxia protocols.If the findings in piglets' brains (to be presented at the Satellite meeting) are the same as those in the adult rat brain, the greater availability of functional MOR as compared to NK-1R during hypoxia may explain the attenuated ventilatory response to repeated hypoxia during development in piglets.
Chronic 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.
Chronic post-ischemic pain (CPIP) is an animal model of CRPS-I developed using a 3-h ischemia–reperfusion injury of the rodent hind paw. The contribution of local endothelin to nociception has been evaluated in CPIP mice by measuring sustained nociceptive behaviors (SNBs) following intraplantar injection of endothelin-1 or -2 (ET-1, ET-2). The effects of local BQ-123 (ETA-R antagonist), BQ-788 (ETB-R antagonist), IRL-1620 (ETB-R agonist) and naloxone (opioid antagonist) were assessed on ET-induced SNBs and/or mechanical and cold allodynia in CPIP mice. ETA-R and ETB-R expression was assessed using immunohistochemistry and Western blot analysis. Compared to shams, CPIP mice exhibited hypersensitivity to local ET-1 and ET-2. BQ-123 reduced ET-1- and ET-2-induced SNBs in both sham and CPIP animals, but not mechanical or cold allodynia. BQ-788 enhanced ET-1- and ET-2-induced SNBs in both sham and CPIP mice, and cold allodynia in CPIP mice. IRL-1620 displayed a non-opioid anti-nociceptive effect on ET-1- and ET-2-induced SNBs and mechanical allodynia in CPIP mice. The distribution of ETA-R and ETB-R was similar in plantar skin of sham and CPIP mice, but both receptors were over-expressed in plantar muscles of CPIP mice. This study shows that ETA-R and ETB-R have differing roles in nociception for sham and CPIP mice. CPIP mice exhibit more local endothelin-induced SNBs, develop a novel local ETB-R agonist-induced (non-opioid) analgesia, and exhibit over-expression of both receptors in plantar muscles, but not skin. The effectiveness of local ETB-R agonists as anti-allodynic treatments in CPIP mice holds promise for novel therapies in CRPS-I patients.
Abstract Background First-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients. Methods/design This is a study protocol for a randomized, double-blind, placebo-controlled, phase II clinical trial with a cross-over design. It is a single-centered, 5-week study that will enroll a total of 32 patients with post-traumatic peripheral neuropathic pain. Patients will be treated topically with either a combination of clonidine and pentoxifylline or placebo for a period of 2 weeks each, in randomly assigned order across patients, with an intervening washout period of 1 week. The primary outcome measures of the study are the intensity of spontaneous pain recorded daily in a pain diary with a visual analog scale, and the degree of mechanical allodynia evoked by a brush stimulus. The secondary outcome measures of the study include scores of pain relief and change in the area of punctate hyperalgesia. This trial has been prospectively registered with ClinicalTrials.gov on November 1, 2017. ClinicalTrials.gov Identifier: NCT03342950 . Discussion The analgesic use of topical treatment with clonidine and pentoxifylline in combination has not been investigated in post-traumatic neuropathic pain. This study could generate the first evidence for the efficacy and safety of the formulation in alleviating pain in patients with neuropathic pain. Furthermore, this trial will provide objective grounds for the investigation of other agents that enhance tissue oxygenation in the topical treatment of peripheral neuropathic pain. Trial registration This trial has been registered with ClinicalTrials.gov owned by NIH’s US National Library of Medicine. ClinicalTrials.gov NCT03342950 . Registered on November 1, 2017 (trial was prospectively registered). Protocol version and identifiers This is protocol version 5, dated June 2018. McGill University Health Center (MUHC) Reaseach Ethics Board (REB) identification number: TTNP 2018-3906.
Chronic pain has been shown to depend on nociceptive sensitization in the spinal cord, and while multiple mechanisms involved in the initiation of plastic changes have been established, the molecular targets which maintain spinal nociceptive sensitization are still largely unknown. Building upon the established neurobiology underlying the maintenance of long-term potentiation in the hippocampus, this present study investigated the contributions of spinal atypical protein kinase C (PKC) isoforms PKCι/λ and PKMζ and their downstream targets (p62/GluA1 and NSF/GluA2 interactions, respectively) to the maintenance of spinal nociceptive sensitization in male and female rats.Pharmacological inhibition of atypical PKCs by ZIP reversed established allodynia produced by repeated intramuscular acidic saline injections in male animals only, replicating previously demonstrated sex differences. Inhibition of both PKCι/λ and downstream substrates p62/GluA1 resulted in male-specific reversals of intramuscular acidic saline-induced allodynia, while female animals continued to display allodynia. Inhibition of NSF/GluA2, the downstream target to PKMζ, reversed allodynia induced by intramuscular acidic saline in both sexes. Neither PKCι/λ, p62/GluA1 or NSF/GluA2 inhibition had any effect on formalin response for either sex.This study provides novel behavioural evidence for the male-specific role of PKCι/λ and downstream target p62/GluA1, highlighting the potential influence of ongoing afferent input. The sexually divergent pathways underlying persistent pain are shown here to converge at the interaction between NSF and the GluA2 subunit of the AMPA receptor. Although this interaction is thought to be downstream of PKMζ in males, these findings and previous work suggest that females may rely on a factor independent of atypical PKCs for the maintenance of spinal nociceptive sensitization.
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