OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel m...OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel multifunctional agonist for opioid and neuropeptide FF(NPFF) receptors named DN-9.The present study was conducted to evaluate the pharmacological activities of DN-9 after peripheral administration.METHODS Antinociceptive activities of subcutaneous DN-9 were investigated in mouse models of acute inflammatory and neuropathic pain.Furthermore,the side-effects of DN-9 were evaluated after peripheral injection in rotarod,antinociceptive tolerance,abuse and gastrointestinal transit tests.RESULTS Subcutaneous DN-9 dose-dependently produced antinociception via peripheral mu-and kappa-opioid receptors,independent of delta-opioid and NPFF receptors,in the tail-flick assay.Similarly,a dose-dependent antinociceptive effect of DN-9 was mediated via peripheral opioid receptors in other inflammatory and neuropathic pain models.Repeated treatment with DN-9 produced antinociceptive effects without a loss of potency in various models of acute,inflammatory and neuropathic pain.DN-9 maintained potent analgesia in morphine-tolerant mice.The gastrointestinal motility inhibition and abuse properties of DN-9 were significantly reduced after subcutaneous injection compared to morphine.DN-9 did not significantly influence the motor coordination of mice.CONCLUSION Subcutaneous administration of DN-9 produces potent analgesic activities with minimal side effects.These data strengthen the therapeutic potential of peripherally acting opioids with multifunctional agonistic properties that are active in a broad range of experimental pain models after peripheral delivery.展开更多
Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （...Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （NSAIDs）, or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic （intraperitoneal） administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.展开更多
Good perioperative analgesia following total knee arthroplasty facilitates rehabilitation and may reduce hospital stay. We present the patient analgesic requirements and rehabilitation of a prospective single surgeon ...Good perioperative analgesia following total knee arthroplasty facilitates rehabilitation and may reduce hospital stay. We present the patient analgesic requirements and rehabilitation of a prospective single surgeon series after the introduction of a multimodal drug injection during his total knee arthroplasty. Basic epidemiological data as well as analgesic, antiemetic requirements and time to straight leg raised was collected on 27 consecutive patients (group 1) whom received the multimodal drug injection, consisting of levobupivacaine, ketorolac and adrenaline at the time of their total knee arthroplasty under spinal anaesthesia. Their rehabilitation was compared to a retrospective review of patients who were case matched by age and sex (group 2n = 26), whom had received the unit standard of spinal anaesthetic and a femoral and sciatic block at the time of their operation. Patients in group 1 had significantly lower analgesic and antiemetic requirements than group 2. Group 1 also had a significantly shorter hospital stay. We have demonstrated that periarticular multimodal drug injection can improve perioperative analgesia and mobilisation following total knee arthroplasty as well as reducing opioid requirements and side effects.展开更多
基金National Natural Science Foundation of China(8167328281273355).
文摘OBJECTIVE Considerable effort has recently been directed at developing multifunctional opioid drugs as an alternative strategy to minimize the unwanted side effects of opioid analgesics.We recently developed a novel multifunctional agonist for opioid and neuropeptide FF(NPFF) receptors named DN-9.The present study was conducted to evaluate the pharmacological activities of DN-9 after peripheral administration.METHODS Antinociceptive activities of subcutaneous DN-9 were investigated in mouse models of acute inflammatory and neuropathic pain.Furthermore,the side-effects of DN-9 were evaluated after peripheral injection in rotarod,antinociceptive tolerance,abuse and gastrointestinal transit tests.RESULTS Subcutaneous DN-9 dose-dependently produced antinociception via peripheral mu-and kappa-opioid receptors,independent of delta-opioid and NPFF receptors,in the tail-flick assay.Similarly,a dose-dependent antinociceptive effect of DN-9 was mediated via peripheral opioid receptors in other inflammatory and neuropathic pain models.Repeated treatment with DN-9 produced antinociceptive effects without a loss of potency in various models of acute,inflammatory and neuropathic pain.DN-9 maintained potent analgesia in morphine-tolerant mice.The gastrointestinal motility inhibition and abuse properties of DN-9 were significantly reduced after subcutaneous injection compared to morphine.DN-9 did not significantly influence the motor coordination of mice.CONCLUSION Subcutaneous administration of DN-9 produces potent analgesic activities with minimal side effects.These data strengthen the therapeutic potential of peripherally acting opioids with multifunctional agonistic properties that are active in a broad range of experimental pain models after peripheral delivery.
基金supported by the grant from Georgian National Science Foundation,No.GNSF/ST07/6-234
文摘Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （NSAIDs）, or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic （intraperitoneal） administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.
文摘Good perioperative analgesia following total knee arthroplasty facilitates rehabilitation and may reduce hospital stay. We present the patient analgesic requirements and rehabilitation of a prospective single surgeon series after the introduction of a multimodal drug injection during his total knee arthroplasty. Basic epidemiological data as well as analgesic, antiemetic requirements and time to straight leg raised was collected on 27 consecutive patients (group 1) whom received the multimodal drug injection, consisting of levobupivacaine, ketorolac and adrenaline at the time of their total knee arthroplasty under spinal anaesthesia. Their rehabilitation was compared to a retrospective review of patients who were case matched by age and sex (group 2n = 26), whom had received the unit standard of spinal anaesthetic and a femoral and sciatic block at the time of their operation. Patients in group 1 had significantly lower analgesic and antiemetic requirements than group 2. Group 1 also had a significantly shorter hospital stay. We have demonstrated that periarticular multimodal drug injection can improve perioperative analgesia and mobilisation following total knee arthroplasty as well as reducing opioid requirements and side effects.
