Antinociceptive effects of the marine snail peptides conantokin-G and conotoxin MVIIA alone and in combination in rat models of pain.
There are a number of neurologically active ion channel blocking peptides derived from cone snail venom, such as conantokin-G and omega-conotoxin MVIIA. Conantokin-G inhibits NMDA receptors containing the NR2B subunit whereas omega-conotoxin MVIIA blocks N-type Ca(2+) channels. Separately, these peptides induce antinociceptive effects in pre-clinical pain models following intrathecal injection. In the current study, the efficacies of these peptides were determined separately and in combination by intrathecal injection into rats with a spinal nerve ligation, in rats with a spinal cord compression injury and in the formalin test. Separately, both conantokin-G and omega-conotoxin MVIIA dose-dependently attenuated nociceptive responses in all of these models. However, at high antinociceptive doses for both formalin and nerve injury models, omega-conotoxin MVIIA evoked untoward side effects. Using isobolographic analysis, the combination of sub-antinociceptive doses of peptides demonstrated additive antinociception in rats with a nerve ligation and in the formalin test, without apparent adverse side effects. In a model of neuropathic spinal cord injury pain, which is clinically difficult to treat, the combination of conantokin-G and omega-conotoxin MVIIA resulted in robust synergistic antinociception. These data suggest that a combination of these peptides may be analgesic across diverse clinical pains with limited untoward side effects, and particularly potent for reducing spinal cord injury pain.
Hama
Aldric
A
The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, 1095 NW 14th Terrace, R-48, Miami, FL 33136, USA. ahama@med.miami.edu
Sagen
Jacqueline
J
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D020916:Conotoxins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D045442:Rotarod Performance Test; D013997:Time Factors; D020960:omega-Conotoxins / Q000627:therapeutic use*
D000700:Analgesics; D020916:Conotoxins; D020960:omega-Conotoxins; C078452:ziconotide; C055407:conotoxin GV