Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of embryonic CNS neurons to BDNF in vitro causes down-regulation of TrkB protein and mRNA, and an attenuation of functional responses to acute neurotrophin stimulation. In order to investigate ligand-mediated regulation of TrkB in vivo, we infused BDNF into the midbrain, near the periaquaductal grey-dorsal raphe (PAG-DR), or into the olfactory bulb of adult rats. Midbrain infusion of BDNF produced analgesia that was sustained for the duration of BDNF delivery. Analysis of TrkB receptor levels revealed that at the point when the maximal analgesic effect of BDNF was obtained, there was a concommitant 75% decrease in full-length TrkB protein at the infusion site. After discontinuation of infusion, levels of TrkB recovered toward base line. Interestingly, TrkB protein levels were not accompanied by decreased trkB mRNA levels. To determine if BDNF infusion decreased TrkB protein levels in other brain areas and whether trkB mRNA might be down-regulated in the cell bodies of neurons projecting to the infusion site, we infused BDNF into the olfactory bulb. Following a 12-day infusion of BDNF, TrkB protein levels decreased within the bulb to a similar extent as in the PAG-DR. This decrease in receptor protein, however, was not accompanied by decreased trkB mRNA levels in the olfactory cortex, which is afferent to the bulb. Taken together, our data suggest that decreases in TrkB receptor protein at the site of BDNF infusions in the adult brain represent receptor turnover, but this is not associated with altered expression of trkB mRNA or attenuation of the pharmacological effects of BDNF.
 ...
PMID:Effects of BDNF infusion on the regulation of TrkB protein and message in adult rat brain. 918 9

Neurotrophic factors may play key roles in pathophysiological mechanisms of human neuropathies. Nerve growth factor (NGF) is trophic to small-diameter sensory fibers and regulates nociception. This review focuses on sensory dysfunction and the potential of neurotrophic treatments. Genetic neuropathy. Mutations of the NGF high-affinity receptor tyrosine kinase A (Trk A) have been found in congenital insensitivity to pain and anhidrosis; these are likely to be partial loss-of-function mutations, as axon-reflex vasodilatation and sweating can be elicited albeit reduced, suggesting rhNGF could restore nociception in some patients. Leprous neuropathy. Decreased NGF in leprosy skin may explain cutaneous hypoalgesia even with inflammation and rhNGF may restore sensation, as spared nerve fibers show Trk A-staining. Diabetic neuropathy. NGF is depleted in early human diabetic neuropathy skin, in correlation with dysfunction of nociceptor fibers. We proposed rhNGF prophylaxis may prevent diabetic foot ulceration. Clinical trials have been disappointed, probably related to difficulty delivering adequate doses and need for multiple trophic factors. NGF and glial cell line-derived neurotrophic factor (GDNF) are both produced by basal keratinocytes and neurotrophin (NT-3) by suprabasal keratinocytes: relative mRNA expression was significantly lower in early diabetic neuropathy skin compared to controls, for NGF (P < 0.02), BDNF (P < 0.05), NT-3 (P < 0.05), GDNF (< 0.02), but not NT4/5, Trk A or p75 neurotrophin receptor (all P > 0.05). Posttranslational modifications of mature and pro-NGF may also affect bioactivity and immunoreactivity. A 53 kD band that could correspond to a prepro-NGF-like molecule was reduced in diabetic skin. Traumatic neuropathy and pain. While NGF levels are acutely reduced in injured nerve trunks, neuropathic patients with chronic skin hyperalgesia and allodynia show marked local increases of NGF levels; here anti-NGF agents may provide analgesia. Physiological combinations of NGF, NT-3 and GDNF, to mimic a 'surrogate target organ', may provide a novel 'homeostatic' approach to prevent the development and ameliorate intractable neuropathic pain (e.g., at painful amputation stumps).
 ...
PMID:Neurotrophic factors and their receptors in human sensory neuropathies. 1469 81

This meeting presented a large array of high quality neuroscience research, some of which held possible relevance for therapeutic development. The potential use of multipotent neural stem cells harvested from adult brain for transplantation and regeneration therapy was highlighted, as was the increasingly central role of the p75 neurotrophin receptor in regulating neuronal cell death. Of particular interest were strategies for the prevention of neuronal death by systemic administration of p75 receptor antisense oligonucleotides. Other significant data included a possible synergy between prostaglandin receptors and opioid receptors in cellular responses, thought to underlie pain perception and opioid analgesia. Groups in Melbourne, Brisbane and Bath, UK, have isolated novel alpha-conotoxins from Conus marine snails, and characterized their effects on neuronal nicotinic acetylcholine receptors (nAChRs), highlighting their subunit specificity and effects on synaptic transmission. While none of these findings are close to effective clinical use as yet, they hold great promise for the future, underlining the necessity for basic research as a starting point for novel therapies.
 ...
PMID:Australian Neuroscience Society--20th Annual Meeting. 30 January-2 February 2000, Melbourne, Australia. 1610 Jun 78

alpha2-Adrenoceptor (AR) agonists increase in analgesic potency and efficacy after peripheral nerve injury, and their effects are blocked by neuronal nitric oxide synthase (nNOS) inhibitors and M4 muscarinic receptor antagonists only after injury. We tested whether nNOS and M4 muscarinic receptors are co-expressed in the spinal cord, and whether destruction of a subset of sensory afferents which are essential to alpha2-AR analgesia would also destroy nNOS and M4 receptor expression. Male Sprague-Dawley rats underwent left L5 and L6 spinal nerve ligation. Lumbar spinal cord was removed and immunostained for M4 muscarinic receptors and nNOS alone and for co-expression. Others received intrathecal injection of saporin linked to an antibody to the neurotrophin receptor p75(NTR), which eliminates cells expressing this receptor and the analgesic effects of alpha2-AR agonists. nNOS staining of fibers in the superficial dorsal horn was dramatically increased after spinal nerve ligation, and this was abolished by saporin linked anti-p75(NTR) treatment. In contrast, nNOS staining in dorsal horn neurons was unaltered by these manipulations. M4 receptors were present on neurons in the dorsal horn, some of which co-expressed nNOS, but their pattern of expression was not altered by these manipulations. Peripheral nerve injury increases nNOS expression in fibers in the superficial dorsal horn, some of which likely express p75(NTR), and alpha2-AR agonists may reduce injury-induced sensitization by activation of nNOS in these fibers In contrast, changes in nNOS and M4 receptor location on spinal cord neurons are not responsible for increased analgesic potency of alpha2-AR agonists after nerve injury.
 ...
PMID:Neuronal nitric oxide synthase is upregulated in a subset of primary sensory afferents after nerve injury which are necessary for analgesia from alpha2-adrenoceptor stimulation. 1711 51

Repeated exposure to opioid drugs can lead to the development of tolerance, which manifests as a reduction in analgesic potency, and physical dependence, a response indicated by a withdrawal syndrome. Accumulating evidence suggests that the nerve growth factor (NGF) family of neurotrophins may have an important modulatory role in the induction of opioid analgesia and opioid addiction. Because neurotrophins universally bind the p75 neurotrophin receptor (p75NTR), we investigated whether the activity of this receptor is involved in the development of opioid analgesic tolerance and physical dependence. We found that in both the wild-type and p75NTR-/- mice an acute systemic (i.p.) injection of morphine produced a maximal analgesic response as measured by the thermal tail-immersion test. Repeated injection of morphine over 5 days in wild-type mice resulted in a progressive decline of the analgesic effect and a concomitant loss of the agonist potency, reflecting development of morphine tolerance. However, the loss of morphine analgesia was not observed in p75NTR-/- mice. In the second part of this study, mice were given escalating doses of systemic (i.p.) morphine over 5 days and subsequently challenged with the opioid receptor antagonist naloxone. This challenge precipitated a robust withdrawal syndrome that was comparable in wild-type mice and p75NTR-/- mice. The findings suggest that p75NTR activity plays a critical role in the development of opioid analgesic tolerance but not in the induction or the expression of opioid physical dependence.
 ...
PMID:Attenuation of opioid analgesic tolerance in p75 neurotrophin receptor null mutant mice. 1911 89

Nerve growth factor (NGF), an essential peptide for sensory neurons, seems to have opposite effects when administered peripherally or directly to the central nervous system. We investigated the effects of 7-days intrathecal (i.t.) infusion of NGF on neuronal and glial spinal markers relevant to neuropathic behavior induced by chronic constriction injury (CCI) of the sciatic nerve. Allodynic and hyperalgesic behaviors were investigated by Von Frey and thermal Plantar tests, respectively. NGF-treated animals showed reduced allodynia and thermal hyperalgesia, compared to control animals. We evaluated on lumbar spinal cord the expression of microglial (ED-1), astrocytic (GFAP and S-100beta), and C- and Adelta-fibers (SubP, IB-4 and Cb) markers. I.t. NGF treatment reduced reactive astrocytosis and the density of SubP, IB4 and Cb positive fibers in the dorsal horn of injured animals. Morphometric parameters of proximal sciatic nerve stump fibers and cells in DRG were also analyzed in CCI rats: myelin thickness was reduced and DRG neurons and satellite cells appeared hypertrophic. I.t. NGF treatment showed a beneficial effect in reversing these molecular and morphological alterations. Finally, we analyzed by immunohistochemistry the expression pattern of neurotrophin receptors TrkA, pTrkA, TrkB and p75(NTR). Substantial alterations in neurotrophin receptors expression were observed in the spinal cord of CCI and NGF-treated animals. Our results indicate that i.t. NGF administration reverses the neuro-glial morphomolecular changes occurring in neuropathic animals paralleled by alterations in neurotrophin receptors ratio, and suggest that NGF is effective in restoring homeostatic conditions in the spinal cord and maintaining analgesia in neuropathic pain.
 ...
PMID:Intrathecal NGF administration reduces reactive astrocytosis and changes neurotrophin receptors expression pattern in a rat model of neuropathic pain. 1958 33

The neurotrophin nerve growth factor (NGF) has been implicated as a key mediator of chronic pain. NGF binds the tropomysin receptor kinase A (TrkA) and p75, resulting in the activation of downstream signaling pathways that have been linked to pro-nociception. While anti-NGF antibodies have demonstrated analgesia both preclinically and in patients, the mechanism of action of these agents remains unclear. We describe ligands targeting NGF, its receptors, and downstream/related targets. This Perspective highlights large and small molecule approaches to targeting the NGF-TrkA pathway both extra- and intracellularly. In addition, we present a strategic framework for future drug discovery efforts in this pathway beyond the targeting of NGF or its receptors. While existing tools have greatly informed NGF-mediated signaling, ongoing and future pathway research may help focus new drug discovery efforts on key novel targets and mechanisms. This may result in highly differentiated therapeutics with greater efficacy and/or improved safety profiles.
 ...
PMID:Targeting the Nerve Growth Factor (NGF) Pathway in Drug Discovery. Potential Applications to New Therapies for Chronic Pain. 2777 99

Nerve growth factor (NGF) is a neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system and that exerts its effects on neurons by signalling through tyrosine kinase receptors. Antibodies that inhibit the function of NGF and small molecule inhibitors of NGF receptors have been developed and tested in clinical studies to evaluate the efficacy of NGF inhibition as a form of analgesia in chronic pain states including osteoarthritis and chronic low back pain. Clinical studies in individuals with painful knee and hip osteoarthritis have revealed that NGF inhibitors substantially reduce joint pain and improve function compared with NSAIDs for a duration of up to 8 weeks. However, the higher tested doses of NGF inhibitors also increased the risk of rapidly progressive osteoarthritis in a small percentage of those treated. This Review recaps the biology of NGF and the studies that have been performed to evaluate the efficacy of NGF inhibition for chronic musculoskeletal pain states. The adverse events associated with NGF inhibition and the current state of knowledge about the mechanisms involved in rapidly progressive osteoarthritis are also discussed and future studies proposed to improve understanding of this rare but serious adverse event.
 ...
PMID:The evolution of nerve growth factor inhibition in clinical medicine. 3321 44