Analgesic Responses to I.V. Lignocaine

Mitchell

2007

Pain

Capsaicin elicits burning pain via the activation of the vanilloid receptor (TRPV1). Intriguingly, several reports showed that capsaicin also inhibits Na + currents but the mechanisms remain unclear. To explore this non-TRPV1 action we applied capsaicin to HEK293 cells stably expressing inactivation-deficient rat skeletal muscle Na + mutant channels (rNav1.4-WCW). Capsaicin elicited a conspicuous time-dependent block of inactivation-deficient Na + currents. The 50% inhibitory concentration (IC 50 ) of capsaicin for open Na + channels at +30 mV was measured 6.8 ± 0.6 μM (n = 5), a value that is 10-30 times lower than those for resting (218 μM) and inactivated (74 μM) wildtype Na + channels. On-rate and off-rate constants for capsaicin open-channel block at +30 mV were estimated to be 6.37 μM −1 s −1 and 34.4 s −1 , respectively, with a calculated dissociation constant (K D ) of 5.4 μM. Capsaicin at 30 μM produced ~70% additional use-dependent block of remaining rNav1.4-WCW Na + currents during repetitive pulses at 1 Hz. Site-directed mutagenesis showed that the local anesthetic receptor was not responsible for the capsaicin block of the inactivation-deficient Na + channel. Interestingly, capsaicin elicited little time-dependent block of batrachotoxin-modified rNav1.4-WCW Na + currents, indicating that batrachotoxin prevents capsaicin binding. Finally, neuronal open Na + channels endogenously expressed in GH 3 cells were as sensitive to capsaicin block as rNav1.4 counterparts. We conclude that capsaicin preferentially blocks persistent late Na + currents, probably via a receptor that overlaps the batrachotoxin receptor but not the local anesthetic receptor. Drugs that target such a non-TRPV1 receptor could be beneficial for patients with neuropathic pain.

“…Such an analgesic pathway has been observed clinically and experimentally after i.v. lidocaine injection (Boas et al, 1982;Devor et al, 1992). Our results shown in Fig.…”

Section: The Non-trpv1 Capsaicin Receptor Site In the Open Na + Channmentioning

confidence: 50%

Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel

Mitchell

2007

Pain

“…Lidocaine and other sodium channel blockers have been used in the treatment of chronic pain (Boas et al, 1982;Chabal et al, 1989a). An expanding body of evidence suggests that it is possible pharmacologically to block some types of sodium channels while leaving other types unblocked; for example, it is possible pharmacologically to block the persistent sodium current that mediates damaging sodium influx in the anoxic optic nerve while leaving the fast sodium current, which underlies action potential electrogenesis, unblocked (Stys et al, 1992).…”

Section: Chronic Painmentioning

confidence: 99%

“…Spinal sensory neurons become hyperexcitable and generate spontaneous impulses after injury in experimental animals (Wall and Gutnick, 1974;Lisney and Devor, 1987;Matzner and Devor, 1994) and humans (Nystrom and Hagbarth, 1981;Nordin et al, 1984). Interestingly, anticonvulsants and local anesthetics have been used at concentrations known to act on sodium channels to manage chronic pain in humans (Boas et al, 1982;Chabal et al, 1989a;Chabal et al, 1992;Galer et al, 1993;Appelgren et al, 1996). Devor (1992, 1994) proposed that the hyperexcitability associated with chronic pain results from an increase in sodium channel density at the site of injury.…”

mentioning

confidence: 99%

Downregulation of Tetrodotoxin-Resistant Sodium Currents and Upregulation of a Rapidly Repriming Tetrodotoxin-Sensitive Sodium Current in Small Spinal Sensory Neurons after Nerve Injury

1997

Clinical and experimental studies have shown that spinal sensory neurons become hyperexcitable after axonal injury, and electrophysiological changes have suggested that this may be attributable to changes in sodium current expression. We have demonstrated previously that sodium channel ␣-III mRNA levels are elevated and sodium channel ␣-SNS mRNA levels are reduced in rat spinal sensory neurons after axotomy. In this study we show that small (C-type) rat spinal sensory neurons express sodium currents with dramatically different kinetics after axotomy produced by sciatic nerve ligation. Uninjured C-type neurons express both slowly inactivating tetrodotoxinresistant (TTX-R) sodium current and a fast-inactivating tetrodotoxin-sensitive (TTX-S) current that reprimes (recovers from inactivation) slowly. After axotomy, the TTX-R current density was greatly reduced. No difference was observed in the density of TTX-S currents after axotomy, and their voltage dependence was not different from controls. However, TTX-S currents in axotomized neurons reprimed four times faster than control TTX-S currents. These data indicate that axotomy of spinal neurons is followed by downregulation of TTX-R current and by the emergence of a rapidly repriming TTX-S current and suggest that this may be attributable to the upregulation of a sodium channel isoform that was unexpressed previously in these cells. These axotomy-induced changes in sodium currents are expected to alter excitability substantially and could underlie the molecular pathogenesis of some chronic pain syndromes associated with injury to the axons of spinal sensory neurons.Key words: sodium channel; sodium current; chronic pain; axotomy; dorsal root ganglion; excitability Although chronic pain affects Ͼ60% of spinal cord injury patients (Knutsdottir, 1993;Levi et al., 1995;Subbarao et al., 1995), its pathophysiology is not well understood. One possibility is that nociceptive spinal sensory neurons generate inappropriate activity after injury. Spinal sensory neurons become hyperexcitable and generate spontaneous impulses after injury in experimental animals (Wall and Gutnick, 1974;Lisney and Devor, 1987;Matzner and Devor, 1994) and humans (Nystrom and Hagbarth, 1981;Nordin et al., 1984). Interestingly, anticonvulsants and local anesthetics have been used at concentrations known to act on sodium channels to manage chronic pain in humans (Boas et al., 1982;Chabal et al., 1989a;Chabal et al., 1992;Galer et al., 1993;Appelgren et al., 1996). Devor (1992, 1994) proposed that the hyperexcitability associated with chronic pain results from an increase in sodium channel density at the site of injury. It also has been hypothesized that changes in the kinetics and voltage-dependent characteristics of sodium currents, possibly because of changes in the expression of sodium channel genes, contribute to the ectopic impulse generation and hyperexcitability of spinal sensory (dorsal root ganglion, DRG) neurons after nerve injury Rizzo et al., 1995Rizzo et al., , 1996. DRG neurons posse...

“…These include neoplastic pain (Cavallini & Beltrami, 1968), post-operative pain (McLachlin, 1945; Keats et al, 1951;De Clive-Lowe, 1958;Bartlett & Hutaserani, 1961;Nalda Felipe et al, 1977;De Gaudio et al, 1978;Marchisio, 1980), post-traumatic pain (Schnapp, 1981), neuralgic pain (Boas et al, 1982;Lindblom & Lindstrdm, 1984), muscular pain (Usubiaga et al, 1967;Haldia et al, 1973), adiposa dolorosa (Iwane et al, 1976;Lindstr6m & Lindblom, 1987;Kastrup et al, 'Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Antinociception induced by systemic administration of local anaesthetics depends on a central cholinergic mechanism

Bartolini

Galli

Ghelardini

et al. 1987

British J Pharmacology

The antinociceptive effects of systemically‐administered procaine, lignocaine and bupivacaine were examined in mice and rats by using the hot‐plate, writhing and tail flick tests. In both species all three local anaesthetics produced significant antinociception which was prevented by atropine (5 mg kg−1, i.p.) and by hemicholinium‐3 (1 μg per mouse, i.c.v.), but not by naloxone (3 mg kg−1, i.p.), α‐methyl‐p‐tyrosine (100 mg kg−1, s.c.), reserpine (2 mg kg−1, i.p.) or atropine methylbromide (5.5 mg kg−1, i.p.). Atropine (5 mg kg−1, i.p.) which totally antagonized oxotremorine (40 μg kg−1, s.c.) antinociception did not modify morphine (5 mg kg−1, s.c.) or baclofen (4 mg kg−1, s.c.) antinociception. On the other hand, hemicholinium, which antagonized local anaesthetic antinociception, did not prevent oxotremorine, morphine or baclofen antinociception. Intracerebroventricular injection in mice of procaine (200 μg), lignocaine (150 μg) and bupivacaine (25 μg), doses which were largely ineffective by parenteral routes, induced an antinociception whose intensity equalled that obtainable subcutaneously. Moreover, the i.c.v. injection of antinociceptive doses did not impair performance on the rota‐rod test. Concentrations below 10−10 m of procaine, lignocaine and bupivacaine did not evoke any response on the isolated longitudinal muscle strip of guinea‐pig ileum, or modify acetylcholine (ACh)‐induced contractions. On the other hand, they always increased electrically‐evoked twitches. The same concentrations of local anaesthetics which induced antinociception did not inhibit acetylcholinesterase (AChE) in vitro. On the basis of the above findings and the existing literature, a facilitation of cholinergic transmission by the local anaesthetics is postulated; this could be due to blockade of presynaptic muscarinic receptors.