An Overview of Antinociceptive Tolerance to Non-steroidal Anti-inflammatory Drugs (original) (raw)
Related papers
Georgian medical news, 2010
Several lines of investigations have shown that the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) in the midbrain periaqueductal gray matter (PAG) induces antinociception with some effects of tolerance. Our recent findings also have shown the same effects of tolerance in intraperitoneal (i.p.) injections of analgin (metamizol), ketorolac, and xefocam. Moreover, just recently, we have shown that microinjection of three NSAIDs analgin, ketorolac and xefocam into the central nucleus of amygdala produces tolerance to these drugs and cross-tolerance to morphine. The present study was designed to examine whether together with analgin, microinjection of another type of NSAIDs clodifen, ketorolac and xefocam into the PAG and the nucleus raphe magnus (NRM) leads to the development of tolerance in male rats. The experiments were carried out on experimental and control (with saline) white male rats by the models of tail-flick (TF, to the stimulation of...
Basic neurobiologic mechanisms of pain and analgesia
The American Journal of Medicine, 1983
Information about tissue damaglng, subjectively painful stimuli is transmitted to the central nervous system by specific receptors. Histologically, they are supposed to be free nerve endings connected to the spinal cord by thin myelinated (A 6 or group Ill) and nonmyellnated (C or group IV) flbers. Nociceptive information is transferred to secondary cells mainly in the surface layers (lamina I and II) and the neck (lamina V) of the dorsal horn; it then ascends the anterolateral funlculus contralaterally in axons of the spinothalamic tract. One portion of this tract ends in the ventroposterior and posterior thalamus. It is assumed that it mediates the dlscriminative component of a pain sensation. The emotional-affective component of a pain sensation is supposed to be produced by that portion of the spinothalamic tract that terminates in the intralaminar nuclei and by the spinoreticular tract. The existence of a cortical paln center has not yet been proved, nor is it clear where in the cerebrum pain is consciously felt. The descending paln inhibitlng systems, originating In the brain stem, may block the transfer of nociceptive information at a spinal level, probably using enkephalin as a transmitter. It is probable that they mediate morphine-induced analgesia. Lesions of tissue release endogenous substances, such as serotonln and certain prostaglandins, which sensitize receptors. The analgesic effect of nonsteroidal anti-inflammatory drugs, such as aspirin, can be explained by the inhibition of prostaglandin synthesis and the desensitization of nociceptors.
Bull. Georg. Natl. …, 2008
Recent investigations have shown that in some brain areas, particularly, in the midbrain periaqueductal gray matter (PAG) and rostral ventro-medial medulla (RVM), the microinjection of non-opioid analgesics, metamizol, and lysine-acetylsalicylate, causes antinociception with some effects of tolerance. Our preliminary findings also have shown the same effects of tolerance in intraperitoneal injections of non-steroidal anti-inflammatory drugs (NSAIDs). The present study was designed to examine whether microinjection of analgine, ketorolac and xefocam into the central nucleus of amygdala (Ce) leads to the development of tolerance in rats, and to ascertain whether this nucleus is the pain-modulating pathway through PAG. Our investigation revealed that microinjection of NSAIDs into the Ce both unilaterally (the left side) and bilaterally produced antinociception as indicated by a latency increase in tail flick reflex (TF) compared to controls with saline, on the first experimental day for analgine (p<0.001), ketorolac (p<0.001), and xefocam (p<0.001) respectively. However, when these drugs microinjection subsequent testing also took place on the following days the antinociceptive effects progressively diminished so that on the fifth experimental day the TF latency was similar to that in the rats that received repeated injections of only saline. These results show that alongside with PAG and RVM the Ce is an important site of endogenous antinociceptive system, which triggers the descending pain control mechanism and thus inhibits nociceptive transmission. On the other hand, our data confirm the results of other authors that NSAIDs are in close relation with endogenous opioids and the tolerance to these non-opioid drugs probably depends on opioid tolerance.
Journal of Clinical Investigation, 2010
It has long been appreciated that the experience of pain is highly variable between individuals. Pain results from activation of sensory receptors specialized to detect actual or impending tissue damage (i.e., nociceptors). However, a direct correlation between activation of nociceptors and the sensory experience of pain is not always apparent. Even in cases in which the severity of injury appears similar, individual pain experiences may vary dramatically. Emotional state, degree of anxiety, attention and distraction, past experiences, memories, and many other factors can either enhance or diminish the pain experience. Here, we review evidence for "top-down" modulatory circuits that profoundly change the sensory experience of pain.
Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus
Frontiers in Neuroscience
Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive e...
Neuroscience, 1996
The rostral ventromedial medulla is a critical relay for midbrain regions, including the periaqueductal gray and nucleus cuneiformis, that control nociception at the spinal cord. Opioidcontaining neurons and terminals are concentrated in both the periaqueductal gray and the rostral ventromedial medulla in the rat. However, the function of endogenous opioid peptides within the medulla in pain modulation is unclear. In this study, bicuculline (30-50 ng) or morphine (5 g) microinjected into the periaqueductal gray inhibited the tail-flick reflex and the firing of on-cells (cells that increase firing just before tail flick) in the medulla. Iontophoretically applied naloxone (20 or 30 nA), which blocked the inhibition of on-cell firing induced by iontophoresis of morphine (20 or 30 nA), consistently reduced the on-cell inhibition produced by bicuculline or morphine microinjected into the periaqueductal gray. Naloxone did not reduce the inhibition of on-cell firing induced by iontophoretically applied clonidine (10 or 20 nA), an 2 adrenoceptor agonist. The firing of off-cells (cells that pause in firing just prior to tail-flick) in the medulla was increased by bicuculline applied in the periaqueductal gray and was not affected by naloxone. The present results suggest that when activation of neurons in the periaqueductal gray produces antinociception, endogenous opioid peptides are released in the rostral ventromedial medulla and selectively inhibit on-cells, which presumably have a facilitating action on spinal nociceptive transmission. This action is proposed to be critical for the behavioral antinociception induced by bicuculline or morphine in the periaqueductal gray.
The Perception and Endogenous Modulation of Pain
Scientifica, 2012
Pain is oen perceived an unpleasant experience that includes sensory and emotional/motivational responses. Accordingly, pain serves as a powerful teaching signal enabling an organism to avoid injury, and is critical to survival. However, maladaptive pain, such as neuropathic or idiopathic pain, serves no survival function. Genomic studies of individuals with congenital insensitivity to pain or paroxysmal pain syndromes considerable increased our understanding of the function of peripheral nociceptors, and especially of the roles of voltage-gated sodium channels and of nerve growth factor (NGF)/TrkA receptors in nociceptive transduction and transmission. Brain imaging studies revealed a "pain matrix, " consisting of cortical and subcortical regions that respond to noxious inputs and can positively or negatively modulate pain through activation of descending pain modulatory systems. Projections from the periaqueductal grey (PAG) and the rostroventromedial medulla (RVM) to the trigeminal and spinal dorsal horns can inhibit or promote further nociceptive inputs. e "pain matrix" can explain such varied phenomena as stress-induced analgesia, placebo effect and the role of expectation on pain perception. Disruptions in these systems may account for the existence idiopathic pan states such as bromyalgia. Increased understanding of pain modulatory systems will lead to development of more effective therapeutics for chronic pain. Scienti ca ACC SI SII INS Thalamus AMY PAG A7 PB A6 RVM DRG Peripheral afferent fiber (nociceptor) (a) A6 ACC SI SII INS Thalamus AMY PAG A7 PB RVM DRG Peripheral afferent fiber (nociceptor) (b)
The central nucleus of amygdala is involved in tolerance to the antinociceptive effect of NSAIDs
Health, 2010
Aim: Repeated microinjections of non-opioid analgesics into the midbrain periaqueductal gray matter and rostral ventro-medial medulla induce antinociception with development of tolerance. Antinociception following systemic administration of non-steroidal anti-inflammatory drugs (N SAIDs) also exhibit tolerance. Presently our aim was to investigate the development of tolerance to the antinociceptive effects of NSAIDs analgine, ketorolac, and xefocam microinjected into central nucleus of amygdala (Ce) in rats. Methods: Under anesthesia with thiopental a stainless steel guide cannula was stereotaxically implanted unilaterally or bilaterally into the Ce using stereotaxic atlas coordinates, and anchored to the cranium by dental cement. Five days after surgery, 3 µl of these NSAIDs were injected via the injection cannula while the rat was gently restrained. Twenty min post microinjection, i.e. 10-min before the peak of the drugs' effect is normally reached, animals were tested with tail flick (TF) and hot plate (HP) tests. On the 5th experimental day all animals received a Ce microinjection of morphine. Results: Daily microinjection of NSAIDs into the Ce uni-or bilaterally, produced antinociception with development of complete tolerance over a 5-day period. Following the treatment period, morphine microinjection into the Ce failed to elicit antinociception, indicating cross-tolerance to the antinociceptive effect of N SAIDs. In other words, the "non-opioid tolerant" rats showed cross-tolerance to morphine. Conclusions: Our data confirmed the suggestion that NSAIDs interact with endogenous opioid systems, which likely play a key role in the development of tolerance to the antinociceptive effects of NSA IDs.