dihydropyridines and Pain

The blockade of L-type calcium channels by dihydropyridines, phenylalkylamines and benzothiazepines has been well described and forms the basis of a multibillion dollar market for the treatment of cardiovascular disease and migraine. More recently, neuron-specific calcium channels have become the subject of intense interest regarding their potential as therapeutic targets for the treatment of chronic and neuropathic pain. A number of recently described agents that selectively target neuronal calcium channels have been described and appear promising for a variety of pain conditions.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Electrophysiology; Humans; Ion Channel Gating; Pain

The aim of this prospective study was to assess the effectiveness in healing anal fissure (AF) of lacidipine, a calcium channel blocker with a better tolerability in comparison to other calcium antagonists. Twenty-one consecutive patients (16 women, 76.2%) with AF (16 chronic, situated posteriorly in 17 patients (81.0%), anteriorly in 4) with a mean age of 37.1 years (SD, 13.6, range, 20-6) were treated with oral lacidipine (6 mg daily) and warm sitz baths for 28 days, adding only stool softeners for patients with constipation. Blood pressure, pain scores (assessed from 0 to 10 on a visual analogue scale) and fissure healing were monitored at 14 days, 28 days and 2 months. At the 14-day and 28-day follow-ups, the mean systolic and diastolic pressures were not significantly different from pre-treatment levels. Seven patients (33.3%) developed side effects, but only one, who developed dyplopia, withdrew from the study at the 14-day control (non-compliance rate with treatment, 4.8%). Pain scores were significantly reduced after 14 days and continued to show a significant reduction throughout the treatment period. Three fissures (14.3%) healed by 14 days and a total of 19 (90.4%) after 28 days: among the healed AF no recurrences were seen at the 2-month control. Among the two treatment failures, one was the patient who withdrew from the study at the 14-day control due to dyplopia and the other was a patient who failed to heal up to the 2-month follow-up, although completely asymptomatic. Both patients underwent left lateral sphincterotomy and healed. In conclusion, oral lacedipine is quite well tolerated and may offer a promising alternative treatment for AF.

Topics: Administration, Oral; Adult; Aged; Calcium Channel Blockers; Dihydropyridines; Female; Fissure in Ano; Follow-Up Studies; Humans; Male; Middle Aged; Nifedipine; Pain; Pain Measurement; Prospective Studies; Time Factors

The long-term effects of isradipine on peripheral occlusive vascular disease of the lower limbs were investigated in 23 normotensive patients with stable Fontaine stage IIa disease and with an absolute pain-free interval (treadmill speed 4 km/h, no incline) of 300 - 700 m, and Doppler ankle - arm arterial pressure index of less than 0.80 in at least one leg. Using a double-blind, parallel-group design, patients received either 2.5 mg isradipine twice daily or placebo for 12 months. Both isradipine (n = 11) and placebo (n = 12) increased the absolute pain-free interval mean values; the increases were not significantly different. Similar trends were observed in the mean values for relative pain-free interval and ankle--arm arterial pressure index. In a subgroup of patients with a baseline absolute pain-free interval of greater than 500 m, isradipine (n = 6) significantly (P less than 0.001) increased both the absolute and the relative pain-free intervals and increased the ankle--arm arterial pressure index compared with placebo (n = 7). The favourable effects of long-term isradipine treatment suggest that isradipine could positively interfere with factors involved in the progression of atherosclerotic lesions or improve collateral vessel flow.

Topics: Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Humans; Intermittent Claudication; Isradipine; Middle Aged; Pain; Pilot Projects; Time Factors

The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C- and lightly-myelinated Aδ-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment.. Withdrawal responses of the capsaicin-only or MRS1477-only treated paws were not significantly different from the untreated, contralateral paws. However, rats treated with the combination of capsaicin and MRS1477 exhibited increased withdrawal latency and decreased response intensity consistent with agonist potentiation and inactivation or lesion of TRPV1-containing nerve terminals. The loss of nerve endings was manifested by an increase in levels of axotomy markers assessed by qRT-PCR and colocalization of ATF3 in TRPV1+ cells visualized via immunohistochemistry.. The present observations suggest a novel, non-narcotic, selective, long-lasting TRPV1-based approach for analgesia that may be effective in acute, persistent, or chronic pain disorders.

Topics: Activating Transcription Factor 3; Analgesics; Animals; Capsaicin; Dihydropyridines; Ganglia, Spinal; Immunohistochemistry; Male; Nociception; Pain; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; TRPV Cation Channels

Cilnidipine is a 1,4-dihydropyridine-derived voltage-dependent calcium channel (VDCC) blocker and suppresses N-type VDCC currents in addition to L-type VDCC currents. An earlier investigation has suggested that intrathecally injected cilnidipine produces antinociception by blocking N-type VDCCs in mice. The present study using the rat formalin model examined antinociceptive effects of intrathecally and orally administered cilnidipine to elucidate a putative site of antinociception of cilnidipine, assess the efficacy of oral cilnidipine for pain relief, and clarify the mechanism(s) responsible for the antinociceptive effect of oral cilnidipine. Cilnidipine (whether intrathecal or oral) suppressed nociception in phases 1 and 2 of the formalin model. In addition, the potency of oral cilnidipine to suppress formalin-induced nociception in phase 2 was greater than that of oral gabapentin, a clinically available drug for treatment of neuropathic pain. Cilnidipine elicited antinociceptive effects without neurological side-effects including serpentine-like tail movement, whole body shaking, and allodynia. Such side-effects can be induced by higher doses of intrathecal ziconotide, a clinically available N-type VDCC blocker. In contrast, orally administered nifedipine, an L-type VDCC blocker, had no effect on either phase of formalin-induced nociception. These results suggest that cilnidipine acts on the spinal cord to produce antinociception and is efficacious for pain relief after oral administration with better safety profile than that of ziconotide. Furthermore, the failure of orally administered nifedipine to affect formalin-induced nociception raises the possibility that oral cilnidipine produces antinociception through, at least in part, spinal N-type VDCC blockade.

Topics: Administration, Oral; Amines; Analgesics; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cyclohexanecarboxylic Acids; Dihydropyridines; Formaldehyde; Gabapentin; gamma-Aminobutyric Acid; Male; Models, Animal; Nifedipine; omega-Conotoxins; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord

Cilnidipine is a 1,4-dihydropyridine derived L/N-type calcium channel dual blocker possessing neuroprotective and analgesic effects which are related to its N-type calcium channel inhibitory activity. In order to find specific N-type calcium channel blockers with the least effects on cardiovascular system, we performed structure-activity relationship study on APJ2708, which is a derivative of cilnidipine, and found a promising N-type calcium channel blocker 21b possessing analgesic effect in vivo with a 1600-fold lower activity against L-type calcium channels than that of cilnidipine.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Dihydropyridines; Formaldehyde; Molecular Structure; Pain; Pain Measurement; Rats; Structure-Activity Relationship

We investigated the N-type voltage-dependent calcium channel blocking action of pranidipine, a novel dihydropyridine (DHP) derivative. Pranidipine significantly suppressed KCl-induced intracellular calcium changes ([Ca(2+)](i)) in a dose-dependent fashion in dorsal root ganglion neurons. A patch-clamp investigation revealed a dose-dependent blocking effect on N-type currents. Intrathecal injection of pranidipine significantly shortened the licking time in the late phase of the formalin test, as occurs with cilnidipine and amlodipine, which act on L- and N-type channels. Conversely, nicardipine, which acts exclusively on L-type channels, had no antinociceptive effect. Our results indicate that pranidipine inhibits N-type calcium channels. Furthermore, it exerts an antinociceptive effect, which might be related to an attenuation of synaptic transmission by nociceptive neurons due to the blocking effect of pranidipine on N-type calcium channels in primary nociceptive afferent fibers.

Topics: Animals; Animals, Newborn; Behavior, Animal; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cells, Cultured; Dicarbethoxydihydrocollidine; Dihydropyridines; Dose-Response Relationship, Drug; Formaldehyde; Ganglia, Spinal; Membrane Potentials; Mice; Neurons; Pain; Pain Measurement; Patch-Clamp Techniques; Potassium Chloride; Time Factors

Protective action of cerebrokrast--a derivative from 1,4-dihydropyridine--on the processes of reparative osteogenesis in rats in case of combined action of chronic emotional-pain stress and trauma of mandibular was determined. It is stipulated by a antioxidant properties of cerebrokrast, as well as its stabilizing influence on glycoproteins and calcium homeostasis. The redeived data extend the idea about general-metabolic action of the investigated nootrop at the level of the whole organism and testify worthwhile of its use for prophylaxis of extreme conditions.

Topics: Animals; Antioxidants; Calcium; Chronic Disease; Dihydropyridines; Glycoproteins; Mandibular Injuries; Osteogenesis; Oxidative Stress; Pain; Rats; Rats, Wistar