The NK1-receptor antagonist TKA731 in painful diabetic neuropathy: A randomised, controlled trial

Department of Neurology, Odense University Hospital, Denmark.
European Journal of Pain (Impact Factor: 2.93). 09/2006; 10(6):567-71. DOI: 10.1016/j.ejpain.2005.08.001
Source: PubMed


Substance P is one of the neurotransmitters released by primary nociceptive neurons in the dorsal horn of the spinal cord and it binds postsynaptically to NK(1)-receptors. This receptor is therefore an obvious target for analgesic drugs. The aim of this multicenter, randomised, double-blind, placebo-controlled and parallel-group study was to test if the non-peptide NK(1)-receptor antagonist TKA731 would relieve painful diabetic polyneuropathy. Eighty-seven patients completed a treatment period of 2 weeks' duration with TKA731 (150 mg daily) or placebo preceded by one week for baseline observations. There was no significant difference between TKA731 and placebo in change in pain rating from baseline to study end neither for rating of total pain (mean -13.4 mm vs. -11.6 mm, p = 0.664) nor for change in ratings of different pain symptoms (touch- or pressure-evoked pain, pain paroxysms, steady burning or deep aching pain) (p = 0.169-0.834).

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    • "Proinflammatory cytokines, chemokines, and so forth produced and released from nonneuronal cells (predominantly immune and glial cells) are also important mediators for persistent pain and all are capable of changing the response properties of central pain signaling neurons [23] [24]. Among the factors, SP, one of the neurotransmitters released from the primary nociceptive afferent endings in the dorsal horn of the spinal cord and postsynaptically binds to NK (1)- receptors [25]. CGRP, an important molecule in the spinal nociceptive processing and ensuring response from primary afferents in the spinal dorsal horn, and PGE2, the main product of cyclooxygenases (COX) and a crucial mediator for inflammatory pain sensitization via promoting synaptic transmission within the spinal cord dorsal horn [26], also contribute to the spinal pain processing network. "
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    ABSTRACT: The present study was aimed to determine if cervicospinal substance P (SP) and its neurokinin-1 receptor (NK-1R), calcitonin gene-related peptide (CGRP), cyclooxygenase-1 (COX-1), and prostaglandin E2 (PGE2) were involved in electroacupuncture (EA) analgesia in neck-incision pain rats. EA intervention was applied to bilateral Futu (LI18), Hegu (LI4)-Neiguan (PC6), and Zusanli (ST36)-Yanglingquan (GB34) for 30 min. Cervicospinal SP and CGRP immunoactivity was detected by immunofluorescence technique, NK-1R and COX-1 protein and mRNA expression levels were determined using Western blot and real-time PCR, respectively, and PGE2 content was measured using ELISA. Outcomes indicated that EA of EA-LI18 and LI4-PC6 (not ST36-GB34) significantly suppressed neck-incision induced decrease of thermal pain threshold (P < 0.05). EA stimulation of LI18 and LI4-PC6 markedly inhibited neck-incision induced upregulation of SP and CGRP immunoactivity, NK-1 R and COX-1 mRNA and protein expression levels, as well as the increase of PGE2 content in the dorsal cervicospinal cord (P < 0.05). These findings showed that LI18 and LI4-PC6 EA stimulation-induced downregulation of SP, CGRP, NK-1R, COX-1, and PGE2 levels in the dorsal cervicospinal cord may contribute to their effects in relieving neck-incision pain. This study highlights the targets of EA intervention for reducing post-thyroid-surgery pain for the first time.
    Full-text · Article · Sep 2013 · Evidence-based Complementary and Alternative Medicine
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    • "The prediction that NK1 receptor antagonists would be effective analgesics was supported by a large body of preclinical data (reviewed by Hill and Oliver, 2006). Although CP-99,994 was efficacious in a model of acute third molar extraction (Dionne et al., 1998), subsequent trials of several NK1 receptor antagonists could demonstrate no efficacy against long-standing pain of osteoarthritis, diabetic neuropathy or migraine (Rupniak and Kramer, 1999; Goldstein et al., 2000; Goldstein et al., 2001a; Goldstein et al., 2001b; Sindrup et al., 2006). Of the many explanations proffered for these unexpected findings (Rupniak and Kramer, 1999; Hill, 2000; Urban and Fox, 2000; Laird, 2001), perhaps most significant is the fact that these clinical trials did not ascertain whether the agents were centrally penetrant in humans. "
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    ABSTRACT: The rostral ventromedial medulla (RVM), a central relay in the bulbospinal pathways that modulate nociception, contains high concentrations of substance P (Sub P) and neurokinin-1 (NK1) receptors. However, the function of Sub P in the RVM is poorly understood. This study characterized the actions of Sub P in the RVM in the absence of injury and then used two NK1 receptor antagonists, L-733,060 and L-703, 606, to probe the role of endogenously released Sub P in the development and maintenance of persistent inflammatory nociception of immune or neurogenic origin. In uninjured rats, microinjection of Sub P in the RVM produced a transient thermal antinociception that was attenuated by pretreatment with L-733,060 or L-703,606. It did not alter threshold to withdrawal from tactile stimulation with von Frey filaments. Microinjection of the antagonists alone did not alter paw withdrawal latency (PWL) or threshold suggesting that Sub P is not tonically released in the RVM in the absence of injury. However, microinjection of either antagonist in the RVM was sufficient to reverse heat hyperalgesia 4 h, 4 days or 2 weeks after intraplantar (ipl) injection of complete Freund's adjuvant (CFA). Antagonism of NK1 receptors in the RVM did not prevent or reverse tactile hypersensitivity induced by CFA, but did attenuate that produced by capsaicin. NK1 receptor antagonism did not prevent the development of thermal hyperalgesia, tactile hypersensitivity or spontaneous pain behaviors induced by mustard oil (MO). The results suggest that Sub P has bimodal actions in the RVM and that following inflammatory injury, it can play a critical role as a pronociceptive agent in the development and maintenance of hyperalgesia and tactile hypersensitivity. However, its actions are highly dependent on the stimulus modality and the type of injury, and this may be an additional basis for the poor efficacy of NK1 receptor antagonists in clinical trials.
    Full-text · Article · Nov 2009 · Neuroscience
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    ABSTRACT: Classification of neuropathic pain according to etiology or localization has clear limitations. The discovery of specific molecular and cellular events following experimental nerve injury has raised the possibility of classifying neuropathic pain on the basis of the underlying neurobiological mechanisms. Application of this approach in the clinic is problematic, however, owing to a lack of precise tools to assess symptoms and signs, and difficulties in correlating symptoms and signs with mechanisms. Development and validation of diagnostic methods to identify mechanisms, together with pharmacological agents that specifically target these mechanisms, seems to be the most logical and rational way of improving neuropathic pain treatment.
    Full-text · Article · Mar 2006 · Nature Clinical Practice Neurology
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