Alpha9 nicotinic acetylcholine receptors and the treatment of pain

Abstract

Chronic pain is a vexing worldwide problem that causes substantial disability and consumes significant medical resources. Although there are numerous analgesic medications, these work through a small set of molecular mechanisms. Even when these medications are used in combination, substantial amounts of pain often remain. It is therefore highly desirable to develop treatments that work through distinct mechanisms of action. While agonists of nicotinic acetylcholine receptors (nAChRs) have been intensively studied, new data suggest a role for selective antagonists of nAChRs. α-Conotoxins are small peptides used offensively by carnivorous marine snails known as Conus. A subset of these peptides known as α-conotoxins RgIA and Vc1.1 produces both acute and long lasting analgesia. In addition, these peptides appear to accelerate the recovery of function after nerve injury, possibly through immune mediated mechanisms. Pharmacological analysis indicates that RgIA and Vc1.1 are selective antagonists of α9α10 nAChRs. A recent study also reported that these α9α10 antagonists are also potent GABA-B agonists. In the current study, we were unable to detect RgIA or Vc1.1 binding to or action on cloned GABA-B receptors expressed in HEK cells or Xenopus oocytes. We review the background, findings and implications of use of compounds that act on α9* nAChRs.

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

“…Each of these tested α9α10 antagonists produces long-lasting analgesia after single injection. The α-conotoxins show an increasing effect after repeated administration, suggesting a possible disease-modifying effect (9,27,43). Similar testing of GeXIVA, as well as head-tohead comparisons with these other α9α10 nAChR antagonists, will be of interest.…”

“…The α9α10 nAChR is of increasing interest in biomedicine, and α-conotoxins that block the α9α10 nAChR subtype are analgesic (9,27,(43)(44)(45). The 4.6 nM IC 50 of GeXIVA [1,2] places it among the most potent peptides that target α9α10 nAChRs; the IC 50 s (nanomolar) for α-conotoxins Vc1.1, RgIA, and PeIA are 19, 5.2, and 6.9, respectively (43,46).…”

“…In addition, transcripts for the α9 and/or α10 subunit have been reported in a variety of nonneuronal cells, including immune cells. Reduced function of α9α10 nAChR is associated with a beneficial alteration of immune function in animal models of chronic pain and experimental autoimmune encephalomyelitis (8,9). In vertebrates, the α9 and/or α10 subunit might be a primordial ancestor of the nAChR family (10,11).…”

Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

“…The α-conotoxins represent one such family that specifically target nicotinic acetylcholine receptor (nAChR) subtypes. Owing to the combination of a large variety of nAChR subunit assemblies and subunit-selective α-conotoxins, many potential novel analgesics have recently been identified (Dutton and Craik 2001;Alonso et al 2003;Sandall et al 2003;Lang et al 2005;Satkunanathan et al 2005;Olivera et al 2008;McIntosh et al 2009) α-Conotoxins, including Vc1.1, RgIA, MII and AuIB, have all been reported to potently reverse signs of neuropathic pain, particularly tactile allodynia, in animal models when administered systemically (Satkunanathan et al 2005;Klimis et al 2011).…”

Structure and Activity of α-Conotoxin PeIA at Nicotinic Acetylcholine Receptor Subtypes and GABAB Receptor-coupled N-type Calcium Channels

“…Targeting individual subtypes can potentially result in drug leads with minimal side effects (10,11). For example, the ␣9␣10 nAChR subtype has been proposed as a potential target for pain relief (12,13). So far, the only ␣-conotoxins that have been reported to be potent antagonists of the ␣9␣10 nAChR subtype are PeIA (14), RgIA (15), and Vc1.1 (16).…”