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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of continuous intrathecal infusion of omega-conopeptides in the rat was examined to determine whether antinociception, as measured on the formalin and hot-plate (52.5 degrees C) tests, was altered and whether tolerance developed with chronic infusion of these agents. Infusion of 0.030 and 0.003 nmol/h SNX-111 and 0.290 nmol/h SNX-239 was performed for either 2 days ('acute') or 7 days ('chronic') and was compared to the effect of 20 nmol/h morphine or saline. Both doses of SNX-111 and SNX-239 produced a significant reduction of the response to the hot-plate and formalin tests at both 2 and 7 days of infusion compared to saline infusion. In contrast, morphine only produced a significant effect on day 2, but not on infusion day 7, indicating that tolerance had developed. The effect of SNX-111 was reversible, as shown by a return to nociceptive responses similar to saline-infused rats 2 days after the minipumps had been disconnected after a 7-day infusion period. These data indicate that chronic infusion of omega-conopeptides that block N-type voltage-sensitive calcium channels produce a powerful antinociception, with minimal development of tolerance.
Pain 1995 Jan
PMID:Effect of continuous intrathecal infusion of omega-conopeptides, N-type calcium-channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats. 771 45

Male Sprague-Dawley rats were used to evaluate the antinociceptive properties of the selective N-type voltage-sensitive calcium channel (VSCC) blocker, SNX-111, when the compound is administered spinally by either bolus injection or continuous, constant-rate infusion into the subarachnoid space. SNX-111 produced significant, dose-dependent antinociceptive effects by suppressing both the acute (phase 1: ED50, 14 ng/hr) and tonic (phase 2: ED50, 0.82 ng/hr) phases of the formalin test when it was infused for 72 hr immediately before testing. Phase 2 nociceptive responses were suppressed by bolus injections of 100 ng SNX-111. SNX-111 was approximately 1000-fold more potent than morphine in blocking phase 2 responses when the compounds were administered by intrathecal bolus injection. In rats with an experimentally induced painful peripheral neuropathy, intrathecal bolus injections of 30 to 300 ng SNX-111 blocked mechanical allodynia in a dose-dependent manner. Subacute administration of SNX-111 (1, 10 and 100 ng/hr) by continuous intrathecal infusion produced a reversible blockade of mechanical allodynia without apparent development of tolerance. These results show that: 1) selective N-type VSCC blockers are potent and efficacious antinociceptive agents when they are administered by the spinal route; 2) selective N-type VSCC blockers are effective in rat models of acute, persistent and neuropathic pain; and 3) N-type VSCCs play a significant role in the spinal processing of noxious somatosensory input.
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PMID:Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. 896 47

SNX-111 is the first neuronal N-type, voltage-sensitive calcium channel (VSCC) blocker to enter clinical drug development. Areas of potential therapeutic utility include treatment of nociceptive and neuropathic pain and neuroprotection after ischemic brain injury. The data presented demonstrate that SNX-111 is biologically active in humans and indicate for the first time a neurophysiologic function of N-type VSCCs in humans.
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PMID:Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans. 930 Mar 26

Recent studies suggest that calcium contributes to peripheral neural mechanisms of hyperalgesia associated with nerve damage. In this animal behavioural study, we examined further the contribution of calcium in neuropathic pain by testing whether subcutaneous administration of either a calcium chelating agent or voltage-dependent calcium channel blockers attenuate nerve injury-induced hyperalgesia to mechanical stimulation. Studies were carried out in animals with partially ligated sciatic nerves, an established animal model of neuropathic pain. The nociceptive flexion reflex was quantified using an Ugo Basile Analgesymeter. Partial nerve injury induced a significant decrease in mechanical threshold compared to the sham operated controls. Daily subcutaneous injections of the calcium chelating agent, Quin 2 (20 microgram/2.5 microliter), significantly attenuated the nerve injury-induced hyperalgesia. Similarly, SNX-111, a N-type channel blocker, also significantly attenuated the nerve injury-induced hyperalgesia. SNX-230, a P and/or Q-type channel blocker, and nifedipine, a L-type channel blocker, had no effect on the hyperalgesia to mechanical stimulation. In control experiments, SNX-111 had no effect on mechanical thresholds when administered subcutaneously in either the hindpaw of normal animals or the back of the neck in nerve injury animals. This study shows that neuropathic pain involves a local calcium-dependent mechanism in the receptive field of intact neurons of an injured nerve, since it can be alleviated by subcutaneous injections of either a calcium chelating agent or SNX-111, a N-type calcium channel blocker. These agents may be effective, peripherally acting therapeutic agents for neuropathic pain.
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PMID:Effect of subcutaneous administration of calcium channel blockers on nerve injury-induced hyperalgesia. 972 73

High voltage calcium channels are implicated in nociceptive transmission after nerve injury, capsaicin or formalin injection. The purpose of this study was to investigate the role of calcium channels in secondary heat hyperalgesia associated with acute joint inflammation. After induction of acute inflammation (knee joint injection of kaolin and carrageenan), decreased paw withdrawal latency (PWL) to radiant heat (i.e., secondary heat hyperalgesia), increased guarding of the limb and increased joint circumference occurs. Spinal administration (through a microdialysis fiber placed in dorsal horn) of an N-type calcium channel blocker (MVIIA, SNX 111, ziconotide, 0.001-0.1 mM), before induction of inflammation, prevents the decrease in PWL. Treatment with SNX 111 4 hr after inflammation reverses heat hyperalgesia. A small reduction in spontaneous pain-related behaviors (guarding of the limb) occurs after pre- or post-treatment with SNX 111. Spinal blockade of P/Q-type calcium channels (with omega-agatoxin IVA) had no effect on the decrease in PWL to radiant heat when administered after induction of inflammation. However, pre-treatment with omega-agatoxin IVA prevents secondary heat hyperalgesia. omega-Agatoxin IVA has no effect on spontaneous pain-related behaviors whether administered before or after induction of inflammation. In contrast, pre or post-treatment with nifedipine (L-type calcium channel blocker, 0.01-1.0 mM), had no effect on heat hyperalgesia or spontaneous pain-related behaviors induced by acute inflammation. There were no differences in joint circumference between groups with any treatment. Thus, N-type calcium channels contribute to both the development and maintenance of secondary heat hyperalgesia while P-type calcium channels are only involved during development of hyperalgesia.
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PMID:Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. 976 42

Ziconotide (SNX-111), a selective blocker of neuronal N-type voltage-sensitive calcium channels, is antinociceptive when it is administered intrathecally. It is currently under clinical investigation for the treatment of malignant and non-malignant pain syndromes. The present study was undertaken to compare and contrast antinociceptive properties of ziconotide, morphine and clonidine in a rat model of post-operative pain. Post-operative pain was produced by making a longitudinal incision through the skin, fascia, and muscle of the plantar aspect of the left hindpaw. This procedure produced immediate (0.5 h after surgery) and long-lasting (4-7 days post-surgery) heat hyperalgesia and mechanical allodynia in the injured hindpaw. Pain thresholds in the contralateral hindpaw were unaffected. Administered one day after incisional surgery, intrathecal ziconotide blocked established heat hyperalgesia in the injured hindpaw in a dose-dependent manner yielding an ED(50)4 h) but reversible (<24 h) blockade of established mechanical allodynia. Administered one day after surgery, intrathecal bolus injection of morphine dose-dependently blocked heat hyperalgesia in the injured hindpaw with an ED(50) of 1.6 microg (2.1 nmol) and heat nociceptive responses in the normal hindpaw with an ED(50) of 2.7 microg (3.6 nmol). The effects were immediate and short-lasting (</=1 h). Intravenous bolus injection of 3 mg/kg (1.1 micromol/kg) ziconotide, administered either before or after incisional surgery, had no effect on thermal pain thresholds measured in either the injured or normal hindpaw. In contrast, intraperitoneal injections of 2 mg/kg (2.6 micromol/kg) morphine and 2.5 mg/kg (9.4 micromol/kg) clonidine blocked heat hyperalgesia in the injured hindpaw; morphine, but not clonidine, also elevated thermal (heat) nociceptive response thresholds in the normal hindpaw. The results of this study show that intrathecal ziconotide is antinociceptive in a rat incisional model of post-operative pain and is more potent, longer acting, and more specific in its actions than intrathecal morphine.
Pain 2000 Feb
PMID:Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. 1066 19

For cancer patients who obtain inadequate pain relief with conservative treatment, there is a growing list of effective options for subarachnoid therapy. Morphine and bupivacaine have been the most frequently used drugs for intrathecal infusion, and their use has consistently yielded good results. Despite their effectiveness, however, a therapeutic deficit remains, primarily in the treatment of neuropathic cancer pain. Because of this limitation, more recent research has focused on novel compounds for intrathecal therapy such as clonidine, midazolam, ketamine, and SNX-111. In addition to new drug options, there are various catheter delivery systems from which to choose. In reviewing the literature and experience to date with these various medications and delivery systems, we hope to better aid the clinician in tailoring the best treatment for each patient.
Curr Rev Pain 1999
PMID:Subarachnoid Techniques for Cancer Pain Therapy: When, Why, and How? 1099 75

This review focuses on the advances in the development of N-type calcium channel blockers as analgesic agents over the last 2 years. Firstly, it highlights the clinical progress with SNX-111 (Ziconotide; Elan Pharmaceuticals, Smithfield, RI) and then secondly, it outlines the various approaches being taken by researchers to design orally active, selective, small molecule modulators without the perceived disadvantages associated with SNX-111.
Curr Rev Pain 2000
PMID:Calcium channel blockers and pain therapy. 1106 May 95

Ever since the application in 1980 of morphine for spinal analgesia in patients with refractory cancer pain, spinal infusion therapy has become one of the cornerstones for the management of chronic, medically intractable pain. Initially, spinal infusion therapy was indicated only for patients with cancer pain that could not be adequately controlled with systemic narcotics. However, over the past decade, there has been a significant increase in the number of pumps implanted for the treatment of nonmalignant pain. Indeed, "benign" pain syndromes, particularly failed back surgery syndrome, are the most common indication for intrathecal opiates. As we have gained more experience with this therapy, it has become apparent that even intrathecal opiates, when administered in the long term, can be associated with problems such as tolerance, hyperalgesia, and other side effects. Consequently, long-term efficacy has not been as significant as had been hoped. Because of the difficulties associated with long-term intrathecal opiate therapy, much of the research, both basic and clinical, has focused on developing alternative nonopioid agents to be used either alone or in combination with opiates. Clinical trials have been and continue to be conducted to evaluate drugs such as clonidine, SNX-111, local anesthetics, baclofen, and many other less common agents to determine their efficacy and potential toxicity for intrathecal therapy. This article reviews the agents developed as alternatives to intrathecal opiates.
Curr Pain Headache Rep 2001 Jun
PMID:Neuraxial infusion in patients with chronic intractable cancer and noncancer pain. 1130 12

Agents which decrease conductance of N-type voltage-gated Ca(2+) channels have been shown to attenuate measures of neuropathic pain in animal models and to provide symptom relief in humans. The omega-conotoxins have demonstrated efficacy but have a low therapeutic index. We have investigated the effects of a new omega-conotoxin, CVID (AM-336), and compared them with omega-conotoxin GVIA (SNX-124), omega-conotoxin MVIIA (SNX-111) and morphine in a spinal nerve ligation model of neuropathic pain in the rat. The ED(50) (and 95% CI) for attenuation of tactile allodynia by intrathecal administration for omega-conotoxin CVID, GVIA, MVIIA and morphine was 0.36 (0.27-0.48), 0.12 (0.06-0.24), 0.32 (0.23-0.45) and 4.4 (2.9-6.5) microg/kg, respectively. Only morphine significantly prolonged acute tail flick responses (ED(50) 2.3 (1.1-4.9) microg/kg). Of the omega-conotoxins, omega-conotoxin CVID showed the highest ratio of efficacy to behavioural toxicity. These observations show that intrathecal omega-conotoxins are effective in attenuating tactile allodynia in the rat without significantly affecting acute nociceptive responses. Omega-conotoxin CVID had similar potency to omega-conotoxin MVIIA but showed less toxicity in the therapeutic range.
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PMID:Actions of intrathecal omega-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. 1224 89


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