All animals were housed in the Biological Services Unit, King’s College London; maintained in 12?h day/night cycle with access to food and water; and were allowed acclimatization for 7?days prior to behavioural experiments

All animals were housed in the Biological Services Unit, King’s College London; maintained in 12?h day/night cycle with access to food and water; and were allowed acclimatization for 7?days prior to behavioural experiments. injection of monosodium iodoacetate (MIA) in the left knee joint of AD\mice (TASTPM) and age\ and gender\matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue. Results MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28?days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re\established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD\mice whilst gabapentin was devoid AMG232 of efficacy. TASTPM exhibited elevated plasma level of \endorphin post\MIA which correlated with impaired allodynia. Conclusions These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re\evaluation of opioid analgesic use for management of pain in AD. Significance This study shows attenuated pain\like behaviour in a transgenic mouse model of Alzheimer’s disease due to alterations in the?opioidergic system and central plasticity mechanisms of persistent pain. 1.?Introduction Alzheimer’s disease (AD) is the most common cause of dementia ( 60% of dementia) in the elderly population. Clinically, it is characterized by a global cognitive deficit ranging from loss of memory to impaired judgement and reasoning (Tanzi and Bertram, Tm6sf1 2001). Experience of pain is a key contributor to challenge of care in AD individuals and is often associated with age\related medical comorbidities, commonly musculoskeletal conditions such as osteoarthritis (OA). OA is the most common age\related musculoskeletal condition affecting the elderly population over the age of 50 (Litwic et?al., 2013). Clinical symptoms are primarily chronic pain coupled with joint stiffness and dysfunction (Hunter et?al., 2008). Due to an incomplete understanding of the underlying mechanisms, there are no cure or disease modifying drugs, at present. Currently, the best treatment options are physiotherapy, pain relief (i.e. paracetamol, non\steroidal anti\inflammatory drugs (NSAIDs), and opiates) and surgical joint replacement (Hunter and Felson, 2006). The cause and incidence of chronic pain conditions, in particular OA, are as common in individuals with AD as in the general elderly population. Despite availability of pain treatment options, assessment and treatment of pain in AD is often difficult, which has a negative impact on the quality of life (Corbett et?al., 2012). Under\treated and inappropriate prescribing in this patient group results in reduced mobility, muscle weakness and falls, which consequently has a major detrimental impact on quality of life and is a key contributor to the presentation of neuropsychiatric symptoms such as aggression and mood disorders (Ballard et?al., 2014; Rajkumar et?al., 2017). It remains unclear whether differences observed in reporting and management of pain are a result of impaired memory and ability to communicate; and/or the perception of pain is altered due to progressive degeneration of cortical and sub\cortical regions involved in processing and transmission of nociceptive information (Hyman et?al., 1984; Scherder and Bouma, 2000). AD\associated neuropathological hallmarks, namely, extracellular \amyloid (A) plaques and intracellular neurofibrillary tangles, accompanied by neuroinflammation have been detected in regions involved in pain processing, namely the spinal cord and the thalamus (Schmidt et?al., 2001; Rub et?al., 2002; Aman et?al., 2016). To date, difficulties in assessment AMG232 of pain in individuals with cognitive impairments has been identified; however, there is AMG232 a lack of understanding of underlying mechanisms of pain in this susceptible population (Ballard et?al., 2009; Corbett et?al., 2012). Therefore, a better understanding of the pathophysiological mechanisms underlying development and progression of OA is essential for improving the clinical management of this chronic pain condition in patients with AD. Here, we assessed development of chemically induced OA pain, via an intra\articular administration of monosodium iodoacetate (MIA), in the double\mutant TASTPM transgenic mouse model of AD (Howlett et?al., 2004; Ogbonna et?al., 2013). The TASTPM transgenic mouse strain carries mutant versions of the amyloid precursor protein (APPswe) and presenilin\1 (PS1.M146V) associated with familial forms of AD (Howlett et?al., 2004). Histological and behavioural analysis of these animals has identified pathological characteristics and cognitive alterations from 3 and 6?months of age, respectively, that reflect some aspects of the pathological changes and cognitive defects observed in people with AD (Howlett et?al., 2004, 2008). Specifically, we characterized pain\like behaviour and associated pathological changes in the periphery and.The scale bar represents 200?m. However, from 14 to 28?days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re\established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD\mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of \endorphin post\MIA which correlated with impaired allodynia. Conclusions These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re\evaluation of opioid analgesic use for management of pain in AD. Significance This study shows attenuated pain\like behaviour in a transgenic mouse model of Alzheimer’s disease due to alterations in the?opioidergic system and central plasticity mechanisms of persistent pain. 1.?Introduction Alzheimer’s disease (AD) is the most common cause of dementia ( 60% of dementia) in the elderly population. Clinically, it is characterized by a global cognitive deficit ranging from loss of memory to impaired judgement and reasoning (Tanzi and Bertram, 2001). Experience of pain is a key contributor to challenge of care in AD individuals and is often associated with age\related medical comorbidities, commonly musculoskeletal conditions such as osteoarthritis (OA). OA is the most common age\related musculoskeletal condition affecting the elderly population over the age of 50 (Litwic et?al., 2013). Clinical symptoms are mainly chronic pain in conjunction with joint rigidity and dysfunction (Hunter et?al., 2008). Because of an incomplete knowledge of the root systems, a couple of no treat or disease changing drugs, at the moment. Currently, the very best treatment plans are physiotherapy, treatment (i.e. paracetamol, non\steroidal anti\inflammatory medications (NSAIDs), and opiates) and operative joint substitute (Hunter and Felson, 2006). The reason and occurrence of chronic discomfort conditions, specifically OA, are as common in people with Advertisement as in the overall elderly people. Despite option of pain treatment plans, evaluation and treatment of discomfort in Advertisement is often tough, that includes a negative effect on the grade of lifestyle (Corbett et?al., 2012). Under\treated and incorrect prescribing within this individual group leads to reduced mobility, muscles weakness and falls, which therefore has a main detrimental effect on standard of living and is an integral contributor towards the display of neuropsychiatric symptoms such as for example aggression and disposition disorders (Ballard et?al., 2014; Rajkumar et?al., 2017). It continues to be unclear whether distinctions observed in confirming and administration of pain certainly are a consequence of impaired storage and capability to connect; and/or the conception of pain is normally altered because of intensifying degeneration of cortical and sub\cortical locations involved in handling and transmitting of nociceptive details (Hyman et?al., 1984; Scherder and Bouma, 2000). Advertisement\linked neuropathological hallmarks, specifically, extracellular \amyloid (A) plaques and intracellular neurofibrillary tangles, followed by neuroinflammation have already been detected in locations involved in discomfort processing, specifically the spinal-cord as well as the thalamus (Schmidt et?al., 2001; Rub et?al., 2002; Aman et?al., 2016). To time, difficulties in evaluation of discomfort in people with cognitive impairments continues to be identified; however, there’s a lack of knowledge of root systems of pain within this prone people (Ballard et?al., 2009; Corbett et?al., 2012). As a result, a better knowledge of the pathophysiological systems root development and development of OA is vital for enhancing the clinical administration of the chronic discomfort condition in sufferers with Advertisement. Here, we evaluated advancement of chemically induced AMG232 OA discomfort,.