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
Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is...Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is the phenomenon of central sensitization. Key processes for pain memory stabilizing could be considering processes of peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathologic in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low-threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding non-injured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sym-pathetically maintained pain. Therefore, these persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long lasting synaptic plasticity as the long-term potentialtion at spinal and supra-spinal levels could undergo hyperalgesia and allodynia. The latter could be providing neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief.展开更多
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Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is the phenomenon of central sensitization. Key processes for pain memory stabilizing could be considering processes of peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathologic in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low-threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding non-injured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sym-pathetically maintained pain. Therefore, these persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long lasting synaptic plasticity as the long-term potentialtion at spinal and supra-spinal levels could undergo hyperalgesia and allodynia. The latter could be providing neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief.
