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1.
Medicine (Baltimore) ; 101(41): e31021, 2022 Oct 14.
Article in English | MEDLINE | ID: mdl-36254032

ABSTRACT

Thirty five percent to sixty seven percent of admissions to acute care hospitals from nursing homes are potentially preventable. Limited data exist regarding clinical and cost trajectories post an acute care hospitalization. To describe clinical impact and post-hospitalization costs associated with acute care admissions for nursing home residents. Analysis of population-based data. The 65,996 nursing home residents from a total of 645 nursing homes. Clinical outcomes assessed with the Changes in Health, End-stage disease and Symptoms and Signs (CHESS) scores, and monthly costs. Post-index date, hospitalized residents worsened their clinical conditions, with increases in CHESS scores (CHESS 3 + 24.5% vs 7.6%, SD 0.46), more limitations in activities of daily living (ADL) (86.1% vs 76.0%, SD 0.23), more prescriptions (+1.64 95% CI 1.43-1.86, P < .001), falls (30.9% vs 18.1%, SD 0.16), pressure ulcers (16.4% vs 8.6%, SD 0.37), and bowel incontinence (47.3% vs 39.3%, SD 0.35). Acute care hospitalizations for nursing home residents had a significant impact on their clinical and cost trajectories upon return to the nursing home. Investments in preventive strategies at the nursing home level, and to mitigate functional decline of hospitalized frail elderly residents may lead to improved quality of care and reduced costs for this population. Pre-hospitalization costs were not different between the hospitalized and control groups but showed an immediate increase post-hospitalization (CAD 1882.60 per month, P < .001).


Subject(s)
Activities of Daily Living , Nursing Homes , Aged , Cohort Studies , Frail Elderly , Hospitalization , Humans
2.
BMJ Open ; 11(2): e038484, 2021 02 05.
Article in English | MEDLINE | ID: mdl-33550224

ABSTRACT

BACKGROUND: Improved identification of patients with complex needs early during hospitalisation may help target individuals at risk of delayed discharge with interventions to prevent iatrogenic complications, reduce length of stay and increase the likelihood of a successful discharge home. METHODS: In this retrospective cohort study, we linked home care assessment records based on the Resident Assessment Instrument for Home Care (RAI-HC) of 210 931 hospitalised patients with their Discharge Abstract Database records. We then undertook multivariable logistic regression analyses to identify preadmission predictive factors for delayed discharge from hospital. RESULTS: Characteristics that predicted delayed discharge included advanced age (OR: 2.72, 95% CI 2.55 to 2.90), social vulnerability (OR: 1.27, 95% CI 1.08 to 1.49), Parkinsonism (OR: 1.34, 95% CI 1.28 to 1.41) Alzheimer's disease and related dementias (OR: 1.27, 95% CI 1.23 to 1.31), need for long-term care facility services (OR: 2.08, 95% CI 1.96 to 2.21), difficulty in performing activities of daily living and instrumental activities of daily living, falls (OR: 1.16, 95% CI 1.12 to 1.19) and problematic behaviours such as wandering (OR: 1.29, 95% CI 1.22 to 1.38). CONCLUSION: Predicting delayed discharge prior to or on admission is possible. Characteristics associated with delayed discharge and inability to return home are easily identified using existing interRAI home care assessments, which can then facilitate the targeting of pre-emptive interventions immediately on hospital admission.


Subject(s)
Home Care Services , Patient Discharge , Activities of Daily Living , British Columbia , Hospitals , Humans , Ontario , Retrospective Studies
3.
CMAJ Open ; 7(2): E341-E350, 2019.
Article in English | MEDLINE | ID: mdl-31110112

ABSTRACT

BACKGROUND: Many aging adults undergo progressive loss of autonomy, develop increasingly complex medical needs and experience multiple care transitions. We sought to determine the degree of variation in rates of transfer from home care services and long-term care in several Canadian jurisdictions. METHODS: In this retrospective cohort study, we examined transitions from home care services and long-term care to different possible end states: change in health stability (getting better or worse), transfer to hospital, transfer to another care setting or death. We used standardized interRAI assessments from long-term care and home care linked to hospital records (data from the Discharge Abstract Database and National Ambulatory Care Reporting System) from 2010 to 2016. Multistate modelling was used to adjust for patients with complex health status and transitions in care. RESULTS: We report data for 254 664 patients in home care programs and 162 045 residents in long-term care. Compared with patients in Ontario, patients requiring home care services in Alberta and British Columbia had increased odds of being admitted to hospital regardless of the underlying severity of illness (the adjusted odds ratios [OR] ranged from 2.08 to 3.77 in Alberta and from 1.28 to 1.46 in BC). Residents in long-term care in Alberta and BC had less than half the odds of being transferred to hospital, independent of all other factors, when compared with long-term care residents in Ontario (the adjusted OR ranged from 0.38 to 0.39 in Alberta and from 0.33 to 0.44 in BC). INTERPRETATION: Significant variations in transfer rates were observed between provinces, even after controlling for individual patient characteristics. These results suggest that transfers to hospital are largely driven by health care policies, health care professional practice patterns and available infrastructure rather than individual patient needs.

4.
J Am Med Dir Assoc ; 20(11): 1425-1431.e1, 2019 11.
Article in English | MEDLINE | ID: mdl-30956146

ABSTRACT

OBJECTIVES: To understand how the odds of both adverse and positive transitions vary over the course of episodes of care in nursing homes. DESIGN: Retrospective cohort study of individuals admitted to nursing homes using clinical and administrative Canadian Resident Assessment Instrument version 2 data linked to emergency department and hospital records. SETTING AND PARTICIPANTS: Adults aged 65 years and older, admitted to nursing homes in Ontario, Alberta, British Columbia, and Yukon Territories in Canada, from 2010 to 2015. The sample involved 163,176 individuals with 1,088,336 RAI 2.0 assessments. MEASURES: Data on mortality and hospitalization were obtained from nursing home and hospital records. Multistate Markov models were employed to estimate odds ratios characterizing covariate effects on transitions to different states of health, hospitalization, and death, stratified by day of stay beginning with the initial 90-day period after admission to a nursing home. RESULTS: The first 90 days of stay after admission were characterized by higher odds of both adverse and positive outcomes after adjusting for numerous covariates. Newly admitted residents had greater odds of becoming worse in health instability, being hospitalized, or dying. However, they also had greater odds of being discharged home or improving in health compared with later stages of the episode of care. These associations varied by the resident's Changes in Health, End-Stage Disease, Signs, and Symptoms (CHESS) scores at the start of each 90-day follow-up period, and CHESS was associated with differential rates of death, hospitalization, and discharge home. CONCLUSIONS/IMPLICATIONS: The initial 90-day period after nursing home placement is one in which the likelihood of both adverse and positive changes is elevated for nursing home residents. Special efforts must be taken after admission to identify and respond to risk factors that may increase the resident's odds of negative outcomes. At the same time, there may be a window of opportunity for the person's transition back to the community after a brief nursing home stay.


Subject(s)
Nursing Homes/organization & administration , Outcome Assessment, Health Care , Patient Admission/statistics & numerical data , Patient Satisfaction/statistics & numerical data , Aged , Aged, 80 and over , Canada , Female , Health Status , Humans , Long-Term Care/statistics & numerical data , Male , Models, Statistical , Risk Factors
5.
J Am Med Dir Assoc ; 20(4): 438-443, 2019 04.
Article in English | MEDLINE | ID: mdl-30573437

ABSTRACT

OBJECTIVES: To understand how a heart failure diagnosis and admission health instability predict health transitions and outcomes among newly admitted nursing home residents. DESIGN: Retrospective cohort study of linked administrative data, including the Continuing Care Report System MDS 2.0 for nursing homes, the Discharge Abstract Database for hospitalized patients, and National Ambulatory Care Reporting System to track emergency department visits. SETTING AND PARTICIPANTS: Older adults, aged 65 years and above, admitted to nursing homes in Ontario, Alberta, and British Columbia, Canada, from 2010 to 2016. MEASURES: Mortality and hospitalization were plotted over 1 year. Multistate Markov models were used to estimate adjusted odds ratios (ORs) for transitions to different states of health in stability, hospitalization, and death, stratified by heart failure diagnosis and by interRAI Changes in Health and End-stage disease Signs and Symptoms (CHESS) score, at 90 days following admission to a nursing home. RESULTS: The final sample included 143,067 residents. Adverse events were most common in the first 90 days. A diagnosis of heart failure predicted worsening health instability, hospitalizations, and mortality. The effect of heart failure on hospitalizations and death was strongest for low baseline health instability (CHESS = 0; OR 1.63, 95% confidence interval (CI) 1.58-1.68, and OR 1.71, 95% CI 1.57-1.86, respectively), versus moderate instability (CHESS = 1-2; OR 1.36, 95% CI 1.32-1.39, and OR 1.48, 95% CI 1.41-1.55), versus high instability (CHESS = 3; OR 1.12, 95% CI 1.03-1.23, and OR 1.21, 95% CI 1.11-1.32). The magnitude of the impact of a heart failure diagnosis was greatest for lower baseline health instability. Residents with the highest degree of health instability were also most likely to die in hospital. CONCLUSIONS AND IMPLICATIONS: A diagnosis of heart failure and health instability provide complementary information to predict transfers, deaths, and adverse outcomes. Clearly identifying these at-risk patients may be useful in targeting interventions in nursing homes.


Subject(s)
Health Transition , Heart Failure , Nursing Homes , Aged , Aged, 80 and over , Canada , Databases, Factual , Female , Forecasting , Frail Elderly , Heart Failure/diagnosis , Heart Failure/mortality , Hospitalization/trends , Humans , Male , Markov Chains , Patient Discharge , Retrospective Studies
6.
BMC Res Notes ; 9: 301, 2016 Jun 10.
Article in English | MEDLINE | ID: mdl-27286651

ABSTRACT

BACKGROUND: Strategies such as Choosing Wisely have been established to identify the overuse of interventions considered as low-value. Reduction of low-value practices will require patients to understand why certain interventions are no longer recommended. The objective of this study was to determine whether older adults accept the rationale for and perceive themselves ready to de-adopt annual electrocardiogram testing, imaging for low back pain, the use of antibiotics for sinusitis, the use of sedative-hypnotics for insomnia, and the use of antipsychotics to treat behavioural symptoms of dementia. METHODS: A self-administered iPad survey was distributed to consecutive patients aged 50 years and older, presenting to three primary care outpatient practices in Ontario, Canada. Data from patients who were able and willing to complete the survey while waiting to see their physician were included. The survey queried knowledge, attitudes and behaviours around the targeted low-value interventions, before and after exposure to a Choosing Wisely Canada patient educational brochure on one of these five topics. A subset of patients agreed to participate in a semi-structured interview after their clinic visit. RESULTS: Three-hundred and forty-four patients (mean age 63, range 50-88, 59 % female) read the materials and completed the survey. Forty-eight percent (95 % CI 43-53 %) intended to discuss the information with a healthcare provider. Forty-five percent (95 % CI 40-51 %) expressed a desire to change current low-value practices. Approximately two-thirds of those who indicated they would not change future behaviours explained that it was because they were already espousing the Choosing Wisely values. After reading the Choosing Wisely brochures, knowledge improved independent of age, sex and education in 48 % (95 % CI 38-57 %) of participants about electrocardiogram testing, in 74 % (95 % CI 65-82 %) about use of antipsychotics, in 66 % (95 % CI 52-78 %) about use of antibiotics for sinusitis, in 60 % (95 % CI 46-72 %) about imaging for low back pain, and in 40 % (95 % CI 26-55 %) about sedative-hypnotic use in the elderly. CONCLUSIONS: The majority of primary care patients seem ready to de-adopt low-value practices. Provision of education in clinic waiting rooms can help improve knowledge around unnecessary care.


Subject(s)
Choice Behavior , Health Care Surveys/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Practice Patterns, Physicians'/statistics & numerical data , Primary Health Care/statistics & numerical data , Aged , Aged, 80 and over , Analysis of Variance , Canada , Female , Health Care Surveys/methods , Humans , Logistic Models , Male , Medical Overuse/prevention & control , Middle Aged , Patient Education as Topic/methods , Practice Patterns, Physicians'/standards , Primary Health Care/methods
7.
Pain ; 151(2): 337-344, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20696525

ABSTRACT

Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund's complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cannabinoids/therapeutic use , Inflammation/drug therapy , Neuralgia/drug therapy , Receptor, Cannabinoid, CB1/metabolism , Animals , Benzimidazoles/therapeutic use , Benzoxazines/blood , Benzoxazines/therapeutic use , Calcium Channel Blockers/blood , Calcium Channel Blockers/therapeutic use , Carrageenan/adverse effects , Disease Models, Animal , Dose-Response Relationship, Drug , Freund's Adjuvant/adverse effects , Humans , Inflammation/chemically induced , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Morpholines/blood , Morpholines/therapeutic use , Naphthalenes/blood , Naphthalenes/therapeutic use , Neuralgia/chemically induced , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/deficiency , Receptor, Cannabinoid, CB2/deficiency , Sulfonamides/therapeutic use , Time Factors
8.
J Comp Neurol ; 504(6): 680-9, 2007 Oct 20.
Article in English | MEDLINE | ID: mdl-17722032

ABSTRACT

It is generally accepted that the voltage-gated, tetrodotoxin-sensitive sodium channel, Na(V)1.7, is selectively expressed in peripheral ganglia. However, global deletion in mice of Na(V)1.7 leads to death shortly after birth (Nassar et al. [2004] Proc. Natl. Acad. Sci. U. S. A. 101:12706-12711), suggesting that this ion channel might be more widely expressed. To understand better the potential physiological function of this ion channel, we examined Na(V)1.7 expression in the rat by in situ hybridization and immunohistochemistry. As expected, highest mRNA expression levels are found in peripheral ganglia, and the protein is expressed within these ganglion cells and on the projections of these neurons in the central nervous system. Importantly, we found that Na(V)1.7 is present in discrete rat brain regions, and the unique distribution pattern implies a central involvement in endocrine and autonomic systems as well as analgesia. In addition, Na(V)1.7 expression was detected in the pituitary and adrenal glands. These results indicate that Na(V)1.7 is not only involved in the processing of sensory information but also participates in the regulation of autonomic and endocrine systems; more specifically, it could be implicated in such vital functions as fluid homeostasis and cardiovascular control.


Subject(s)
Autonomic Nervous System/metabolism , Endocrine System/metabolism , Sodium Channels/metabolism , Animals , Cell Line, Transformed , Central Nervous System/metabolism , Humans , Immunohistochemistry/methods , In Situ Hybridization/methods , Male , NAV1.7 Voltage-Gated Sodium Channel , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Sodium Channels/genetics
9.
Hum Mol Genet ; 16(17): 2114-21, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17597096

ABSTRACT

The general lack of pain experience is a rare occurrence in humans, and the molecular causes for this phenotype are not well understood. Here we have studied a Canadian family from Newfoundland with members who exhibit a congenital inability to experience pain. We have mapped the locus to a 13.7 Mb region on chromosome 2q (2q24.3-2q31.1). Screening of candidate genes in this region identified a protein-truncating mutation in SCN9A, which encodes for the voltage-gated sodium channel Na(v)1.7. The mutation is a C-A transversion at nucleotide 984 transforming the codon for tyrosine 328 to a stop codon. The predicted product lacks all pore-forming regions of Na(v)1.7. Indeed, expression of this altered gene in a cell line did not produce functional responses, nor did it cause compensatory effects on endogenous voltage-gated sodium currents when expressed in ND7/23 cells. Because a homozygous knockout of Na(v)1.7 in mice has been shown to be lethal, we explored why a deficiency of Na(v)1.7 is non-lethal in humans. Expression studies in monkey, human, mouse and rat tissue indicated species-differences in the Na(v)1.7 expression profile. Whereas in rodents the channel was strongly expressed in hypothalamic nuclei, only weak mRNA levels were detected in this area in primates. Furthermore, primate pituitary and adrenal glands were devoid of signal, whereas these two glands were mRNA-positive in rodents. This species difference may explain the non-lethality of the observed mutation in humans. Our data further establish Na(v)1.7 as a critical element of peripheral nociception in humans.


Subject(s)
Codon, Terminator/genetics , Mutation , Pain Insensitivity, Congenital/genetics , Sodium Channels/genetics , Animals , Base Sequence , Brain/metabolism , Humans , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Models, Biological , Molecular Sequence Data , NAV1.7 Voltage-Gated Sodium Channel , Pain/genetics , Pain/physiopathology , Pain Insensitivity, Congenital/physiopathology , Pedigree , Phenotype , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Sodium Channels/metabolism
10.
Trends Pharmacol Sci ; 28(1): 23-31, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17150262

ABSTRACT

A cell can regulate how it interacts with its external environment by controlling the number of plasma membrane receptors that are accessible for ligand stimulation. G-protein-coupled receptors (GPCRs) are the largest superfamily of cell surface receptors and have a significant role in physiological and pathological processes. Much research effort is now focused on understanding how GPCRs are delivered to the cell surface to enhance the number of 'bioavailable' receptors accessible for activation. Knowing how such processes are triggered or modified following induction of various pathological states will inevitably identify new therapeutic strategies for treating various diseases, including chronic pain. Here, we highlight recent advances in this field, and provide examples of the importance of such trafficking events in pain.


Subject(s)
Analgesia , Pain/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Opioid, delta/metabolism , Animals , Cell Membrane/metabolism , Humans , Pain/drug therapy , Protein Transport
11.
J Mol Neurosci ; 25(3): 207-14, 2005.
Article in English | MEDLINE | ID: mdl-15800374

ABSTRACT

In recent years, we demonstrated that prolonged (48-h) treatment of rats or mice with selective m-opioid receptor ((mu)OR) agonists induced a translocation of delta-opioid receptors ((delta)ORs) from intracellular compartments to neuronal plasma membranes in the dorsal horn of the spinal cord. It remained to be determined whether this phenomenon also occurred in the brain. To resolve this issue, we analyzed by immunogold histochemistry the subcellular distribution of (delta)ORs in the nucleus accumbens, dorsal neostriatum, and frontal cortex in mice treated or not with morphine (48 h). We observed that prolonged treatment with morphine induced a translocation of (delta)ORs from intracellular to subplasmalemmal and membrane compartments in dendrites from both the nucleus accumbens and the dorsal neostriatum but not from the frontal cortex. We propose that this (mu)OR-(delta)OR interaction might prolong and modulate the sensitivity of neurons to opiates in specific target regions.


Subject(s)
Analgesics, Opioid/pharmacology , Morphine/pharmacology , Neostriatum/drug effects , Nucleus Accumbens/drug effects , Receptors, Opioid, delta/metabolism , Animals , Cell Membrane/metabolism , Cell Membrane/ultrastructure , Female , Frontal Lobe/cytology , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Male , Mice , Mice, Inbred C57BL , Microscopy, Electron , Neostriatum/cytology , Neostriatum/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/ultrastructure , Nucleus Accumbens/cytology , Nucleus Accumbens/metabolism , Protein Transport/drug effects
12.
Int J Biochem Cell Biol ; 36(11): 2153-68, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15313463

ABSTRACT

The neurotensin receptor-3, originally identified as sortilin, is unique among neuropeptide receptors in that it is a single trans-membrane domain, type I receptor. To gain insight into the functionality of neurotensin receptor-3, we examined the neurotensin-induced intracellular trafficking of this receptor in the human carcinoma cell line HT29, which expresses both neurotensin receptor-1 and -3 sub-types. At steady state, neurotensin receptor-3 was found by sub-cellular fractionation and electron microscopic techniques to be predominantly associated with intracellular elements. A small proportion (approximately 10%) was associated with the plasma membrane, but a significant amount (approximately 25%) was observed inside the nucleus. Following stimulation with neurotensin (NT), neurotensin/neurotensin receptor-3 complexes were internalized via the endosomal pathway. This internalization entailed no detectable loss of cell surface receptors, suggesting compensation through either recycling or intracellular receptor recruitment mechanisms. Internalized ligand and receptors were both sorted to the pericentriolar recycling endosome/Trans-Golgi Network (TGN), indicating that internalized neurotensin is sorted to this compartment via neurotensin receptor-3. Furthermore, within the Trans-Golgi Network, neurotensin was bound to a lower molecular form of the receptor than at the cell surface or in early endosomes, suggesting that signaling and transport functions of neurotensin receptor-3 may be mediated through different molecular forms of the protein. In conclusion, the present work suggests that the neurotensin receptor-3 exists in two distinct forms in HT29 cells: a high molecular weight, membrane-associated form responsible for neurotensin endocytosis from the cell surface and a lower molecular weight, intracellular form responsible for the sorting of internalized neurotensin to the Trans-Golgi Network.


Subject(s)
Cell Membrane/metabolism , Endocytosis/physiology , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Protein Transport/physiology , Receptors, Neurotensin/metabolism , Adaptor Proteins, Vesicular Transport , Cell Fractionation , Cell Nucleus/metabolism , Golgi Apparatus/metabolism , HT29 Cells , Humans , Microscopy, Immunoelectron , Neurotensin/metabolism , Signal Transduction/physiology
13.
J Neurosci ; 24(24): 5549-59, 2004 Jun 16.
Article in English | MEDLINE | ID: mdl-15201327

ABSTRACT

An in vivo fluorescent deltorphin (Fluo-DLT) internalization assay was used to assess the distribution and regulation of pharmacologically available delta opioid receptors (deltaORs) in the rat lumbar (L4-5) spinal cord. Under basal conditions, intrathecal injection of Fluo-DLT resulted in the labeling of numerous deltaOR-internalizing neurons throughout dorsal and ventral horns. The distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent with that of deltaOR-expressing neurons, as revealed by in situ hybridization and immunohistochemistry, suggesting that a large proportion of these cells was responsive to intrathecally administered deltaOR agonists. Pretreatment of rats with morphine for 48 hr resulted in a selective increase in Fluo-DLT-labeled perikaryal profiles within the dorsal horn. These changes were not accompanied by corresponding augmentations in either deltaOR mRNA or (125)I-deltorphin-II binding levels, suggesting that they were attributable to higher densities of cell surface deltaOR available for internalization rather than to enhanced production of the receptor. Unilateral dorsal rhizotomy also resulted in increased Fluo-DLT internalization in the ipsilateral dorsal horn when compared with the side contralateral to the deafferentation or to non-deafferented controls, suggesting that deltaOR trafficking in dorsal horn neurons may be regulated by afferent inputs. Furthermore, morphine treatment no longer increased Fluo-DLT internalization on either side of the spinal cord after unilateral dorsal rhizotomy, indicating that microOR-induced changes in the cell surface availability of deltaOR depend on the integrity of primary afferent inputs. Together, these results suggest that regulation of deltaOR responsiveness through microOR activation in this region is linked to somatosensory information processing.


Subject(s)
Morphine/pharmacology , Narcotics/pharmacology , Receptors, Opioid, delta/metabolism , Spinal Cord/metabolism , Animals , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , In Situ Hybridization , Lumbosacral Region , Male , Microscopy, Fluorescence , Oligopeptides/chemistry , Oligopeptides/metabolism , Oligopeptides/pharmacology , Posterior Horn Cells/metabolism , Protein Transport , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/agonists , Receptors, Opioid, delta/biosynthesis , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/metabolism , Rhizotomy , Spinal Cord/anatomy & histology , Up-Regulation
14.
Pain ; 109(3): 266-273, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15157687

ABSTRACT

Previous studies from our laboratory have demonstrated that both chronic inflammatory pain, induced by intraplantar injection of complete Freund's adjuvant (CFA), and prolonged (48 h) stimulation of mu-opioid receptors (muOR) by systemic administration of a variety of selective agonists, resulted in enhanced plasma membrane targeting of delta-opioid receptors (deltaOR) in neurons of the dorsal spinal cord. To determine whether deltaOR trafficking induced by chronic inflammation was dependent on the activation of muOR, we investigated by immunogold cytochemistry the effects of intraplantar CFA injection on the plasma membrane density of deltaOR in muOR knockout (KO) mice. In untreated wild-type (WT) mice, only a small proportion of deltaOR was associated with neuronal plasma membranes in the dorsal horn of the spinal cord. The CFA-induced inflammation produced a significantly higher ratio of plasma membrane to intracellular receptors, as well as a 75% increase in the membrane density of immunoreactive deltaOR, in dendrites of the ipsilateral dorsal horn as compared to untreated mice. This increase in the membrane density of deltaOR was likely due to a recruitment of receptors from intracellular stores since no difference in the overall deltaOR immunolabeling density was evident between CFA-treated and untreated mice. Most importantly, the CFA-induced changes in deltaOR plasma membrane insertion seen in WT animals were not present in the spinal cord of muOR KO mice. These results demonstrate that the integrity of muOR is necessary for CFA-induced changes in deltaOR trafficking to occur and suggest that these changes could be elicited by stimulation of muOR by endogenous opioids released in response to chronic inflammatory pain.


Subject(s)
Inflammation/genetics , Pain/genetics , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/genetics , Animals , Cell Membrane/genetics , Cell Membrane/metabolism , Cell Membrane/ultrastructure , Chronic Disease , Dendrites/metabolism , Dendrites/ultrastructure , Disease Models, Animal , Female , Freund's Adjuvant , Functional Laterality/genetics , Immunohistochemistry , Inflammation/metabolism , Inflammation/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron , Pain/metabolism , Pain/physiopathology , Posterior Horn Cells/metabolism , Posterior Horn Cells/ultrastructure , Protein Transport/drug effects , Protein Transport/genetics , Receptors, Opioid, mu/deficiency , Up-Regulation/drug effects , Up-Regulation/genetics
15.
Endocrinology ; 145(9): 4392-400, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15166125

ABSTRACT

Apelin, a neuropeptide recently identified as the endogenous ligand for the G protein-coupled receptor APJ, is highly concentrated in brain structures involved in the control of body fluid homeostasis including the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. To clarify the implication of apelin in the regulation of water balance, we sought to determine whether apelin colocalized with arginine vasopressin (AVP) in the rat SON and PVN. We also investigated the effects of water deprivation on the levels of apelin within these two nuclei by comparison with those of AVP. Using dual immunolabeling confocal microscopy, we found that a large proportion of apelin-immunoreactive neurons colocalized AVP within both the SON and PVN, but that the two peptides were segregated within distinct subcellular compartments inside these cells. Both the number and labeling intensity of magnocellular apelin-immunoreactive cells increased significantly after 24- or 48-h dehydration, whereas the number and labeling density of AVP-immunoreactive neurons significantly decreased. The dehydration-induced increase in apelin immunoreactivity was markedly diminished by central injection of a selective vasopressin-1 receptor antagonist. Conversely, the effect of dehydration was mimicked by a 16-min intracerebroventricular infusion of AVP, again in a vasopressin-1 receptor antagonist-reversible manner. These results provide additional evidence for the involvement of the neuropeptide apelin in the control of body fluid homeostasis. They further suggest that the dehydration-induced release of AVP from magnocellular hypothalamic neurons may be responsible for the observed increase in immunoreactive apelin levels within the same neurons and thus that the release of one peptide may block that of another peptide synthesized in the same cells.


Subject(s)
Arginine Vasopressin/metabolism , Carrier Proteins/metabolism , Dehydration/metabolism , Hypothalamus, Anterior/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Animals , Antibodies , Apelin , Arginine Vasopressin/immunology , Body Water/metabolism , Carrier Proteins/immunology , Homeostasis/physiology , Intercellular Signaling Peptides and Proteins , Male , Rabbits , Rats , Receptors, Vasopressin/metabolism , Water Deprivation/physiology
16.
J Neurosci ; 23(12): 4888-98, 2003 Jun 15.
Article in English | MEDLINE | ID: mdl-12832511

ABSTRACT

We recently demonstrated that prolonged treatment with morphine increases the antinociceptive potency of the delta-opioid receptor (deltaOR) agonist deltorphin and promotes cell surface targeting of deltaORs in neurons of the dorsal horn of the rat spinal cord (Cahill et al., 2001b). In the present study we examined whether these effects were mediated selectively via muOR. Using the same intermittent treatment regimen as for morphine, we found that methadone and etorphine, but not fentanyl, enhanced [D-Ala2]-deltorphin-mediated antinociception. However, continuous delivery of fentanyl for 48 hr resulted in augmented deltaOR-mediated antinociception when compared with saline-infused animals. Time course studies confirmed that a 48 hr treatment with morphine was necessary for the establishment of enhanced deltaOR-mediated antinociception. The observed increases in deltaOR agonist potency and deltaOR plasma membrane density were reversed fully 48 hr after discontinuation of morphine injections. Wild-type C57BL/6 mice pretreated with morphine for 48 hr similarly displayed enhanced deltaOR-mediated antinociception in a tonic pain paradigm. Accordingly, the percentage of plasma membrane-associated deltaOR in the dorsal horn of the spinal cord, as assessed by immunogold electron microscopy, increased from 6.6% in naive to 12.4% in morphine-treated mice. In contrast, morphine treatment of muOR gene knock-out (KO) mice did not produce any change in deltaOR plasma membrane density. These results demonstrate that selective activation of muOR is critical for morphine-induced targeting of deltaOR to neuronal membranes, but not for basal targeting of this receptor to the cell surface.


Subject(s)
Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/deficiency , Animals , Area Under Curve , Behavior, Animal/drug effects , Cell Membrane/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Etorphine/pharmacology , Female , Fentanyl/administration & dosage , Fentanyl/pharmacology , Male , Methadone/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Morphine/pharmacology , Narcotics/pharmacology , Pain Measurement/drug effects , Posterior Horn Cells/cytology , Posterior Horn Cells/drug effects , Posterior Horn Cells/metabolism , Protein Transport/drug effects , Protein Transport/physiology , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/genetics , Receptors, Opioid, mu/metabolism , Time , Up-Regulation/drug effects
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