ziconotide and Peripheral-Nervous-System-Diseases

Severe chronic pain afflicts a large number of people worldwide but satisfactory relief from such pain is difficult to achieve with drugs that are currently available, and so there is a great need for the development of new, efficacious and safe analgesics. Voltage-gated calcium-permeable ion channels are multi-subunit complexes that regulate neuronal excitability, action-potential firing patterns and neurotransmission in nociceptive pathways. Although multiple subtypes of voltage-gated calcium channels exist, pharmacological and ion-channel gene knockdown approaches in animals have revealed N-type and T-type calcium channels to be particularly attractive molecular targets for the discovery and development of new analgesic drugs. The recent approval of Prialt (Elan Pharmaceuticals) provides the ultimate target validation for N-type calcium channels, namely proof that they are key regulators of nociceptive signaling in humans.

Topics: Acute Disease; Analgesics; Animals; Calcium Channels, N-Type; Calcium Channels, T-Type; Chronic Disease; Humans; omega-Conotoxins; Pain; Peripheral Nervous System Diseases

Topics: Acute Pain; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hyperalgesia; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; omega-Conotoxin GVIA; omega-Conotoxins; Peripheral Nervous System Diseases

A 50-year-old female patient with chronic neuropathic pain in the distribution of the second branch of the trigeminal nerve was unsuccessfully treated over several years. Intrathecal therapy with ziconotide was administered at an initial dose of 0.33 microg/d, which was gradually increased by 0.7 microg/d. Subjective pain on the numeric rating scale was reduced from 9/10 to 3-4/10 at a dose of 6.3 microg/d. Long-term treatment was continued at a ziconotide concentration of 12.5 microg/mL and a daily dose of 3.9 microg/d by a SynchroMed Infusion System (Medtronic, Minneapolis, MN). Pain reduction was maintained in the follow-up observation period over 5 months.

Topics: Amitriptyline; Analgesics; Antidepressive Agents, Tricyclic; Azabicyclo Compounds; Calcium Channel Blockers; Female; Humans; Hypnotics and Sedatives; Injections, Spinal; Long-Term Care; Middle Aged; omega-Conotoxins; Pain Measurement; Peripheral Nervous System Diseases; Piperazines; Trigeminal Neuralgia

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

Topics: Analgesics; Animals; Binding Sites; Butanones; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cerebral Ventricles; Drug Design; In Vitro Techniques; Male; Mice; Pain; Pain Measurement; Pain Threshold; PC12 Cells; Peripheral Nervous System Diseases; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

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.

Topics: Analgesics; Animals; Calcium Channel Blockers; Disease Models, Animal; Formaldehyde; Ion Channel Gating; Male; Neurons; omega-Conotoxins; Pain; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Spinal Cord

In patients and animals with painful peripheral neuropathies, spontaneous ectopic discharge from injured primary afferents is hypothesized to maintain a central state of hyperexcitability that underlies hyperalgesia and allodynia. Temporary suppression of this discharge allows the central state to normalize, such that hyperalgesia and allodynia are absent or reduced until the resumption of the discharge rekindles central hyperexcitability. Previous work suggests that Ca++ channels are involved in the genesis of spontaneous discharge from injured afferents. We applied SNX-111 and SNX-124 (0.1-3.0 micrograms), synthetic homologs of omega-conopeptides (MVIIA and GVIA, respectively) and potent blockers of neuronal N-type voltage-sensitive Ca++ channels, to the site of nerve injury via chronically implanted perineural cannulae in rats with an experimental painful peripheral neuropathy (the chronic constriction injury model). Heat-hyperalgesia and mechano-allodynia were reduced for at least 3 hr. Drug application to a normal nerve had no effect on responses to heat or mechanical stimuli. These results suggest that N-type Ca++ channel blockers may be useful in the treatment of the abnormal pains that occur after nerve injury.

Topics: Animals; Calcium Channel Blockers; Hyperalgesia; Male; omega-Conotoxin GVIA; omega-Conotoxins; Pain; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sciatic Nerve