Reduced nicotinic receptor-mediated antinociception following in vivo antisense knock-down in rat

Reduced nicotinic receptor-mediated antinociception following in vivo antisense knock-down in rat Pharmacological activation of neuronal nicotinic acetylcholine receptors can produce non-opioid antinociception in rodents. However, multiple nAChR subtypes exist, the most abundant of which contain α4 and β2 subunits. The purpose of the present study was to investigate the role of α4-containing nAChRs in mediating nicotinic antinociception using an in vivo antisense strategy. Both i.c.v. infusion and repeated bolus injections into the cerebral aqueduct of an antisense oligonucleotide against the α4 subunit significantly attenuated the antinociceptive effects of the nAChR agonist A-85380 in the paw withdrawal test of acute thermal pain. Rats treated with a scrambled oligonucleotide displayed a full antinociceptive response to A-85380, while discontinuing antisense treatment restored the antinociceptive effects of the nicotinic agonist. Double immunohistochemical labeling revealed near-complete overlap of expression of the serotonin marker tryptophan hydroxylase and the α4 nAChR subunit in the dorsal raphe nucleus. The expression of α4-containing nAChRs by serotonergic neurons in the dorsal raphe offered a means to address nonspecific α4 knock-down, i.e., oligonucleotide-induced neurotoxicity. Immunohistochemical detection of α4 expression was reduced by nearly 50% in the dorsal raphe of antisense-treated rats as compared to either saline or missense-treated controls. In contrast, the expression of tryptophan hydroxylase, as well as, the α7 nAChR subunit in antisense-infused rats was similar to that observed in saline- and missense-treated controls. The results of these studies suggest that α4-containing nAChRs, possibly expressed by serotonergic neurons, are involved in nicotinic-mediated analgesia. However, these data do not eliminate the possibility that other nicotinic subunit combinations may also play a role in antinociception produced by nAChR activation. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Research Elsevier

Reduced nicotinic receptor-mediated antinociception following in vivo antisense knock-down in rat

Loading next page...
 
/lp/elsevier/reduced-nicotinic-receptor-mediated-antinociception-following-in-vivo-9kAb4avmXt
Publisher
Elsevier
Copyright
Copyright © 2000 Elsevier Science B.V.
ISSN
0006-8993
DOI
10.1016/S0006-8993(00)02442-2
Publisher site
See Article on Publisher Site

Abstract

Pharmacological activation of neuronal nicotinic acetylcholine receptors can produce non-opioid antinociception in rodents. However, multiple nAChR subtypes exist, the most abundant of which contain α4 and β2 subunits. The purpose of the present study was to investigate the role of α4-containing nAChRs in mediating nicotinic antinociception using an in vivo antisense strategy. Both i.c.v. infusion and repeated bolus injections into the cerebral aqueduct of an antisense oligonucleotide against the α4 subunit significantly attenuated the antinociceptive effects of the nAChR agonist A-85380 in the paw withdrawal test of acute thermal pain. Rats treated with a scrambled oligonucleotide displayed a full antinociceptive response to A-85380, while discontinuing antisense treatment restored the antinociceptive effects of the nicotinic agonist. Double immunohistochemical labeling revealed near-complete overlap of expression of the serotonin marker tryptophan hydroxylase and the α4 nAChR subunit in the dorsal raphe nucleus. The expression of α4-containing nAChRs by serotonergic neurons in the dorsal raphe offered a means to address nonspecific α4 knock-down, i.e., oligonucleotide-induced neurotoxicity. Immunohistochemical detection of α4 expression was reduced by nearly 50% in the dorsal raphe of antisense-treated rats as compared to either saline or missense-treated controls. In contrast, the expression of tryptophan hydroxylase, as well as, the α7 nAChR subunit in antisense-infused rats was similar to that observed in saline- and missense-treated controls. The results of these studies suggest that α4-containing nAChRs, possibly expressed by serotonergic neurons, are involved in nicotinic-mediated analgesia. However, these data do not eliminate the possibility that other nicotinic subunit combinations may also play a role in antinociception produced by nAChR activation.

Journal

Brain ResearchElsevier

Published: Jul 14, 2000

References

  • Antinociceptive action of nicotine and its methiodide derivatives in mice and rats
    Aceto, M.D.; Awaya, H.; Martin, B.R.; May, E.L.
  • Effects of nicotine and mecamylamine on rat dorsal raphe neurons
    Mihailescu, S.; Palomero–Rivero, M.; Meade–Huerta, P.; Maza–Flores, A.; Drucker–Colin, R.
  • The diversity of neuronal nicotinic acetylcholine receptors
    Sargent, P.
  • An electron microscopic observation of the vesicular acetylcholine transporter-immunoreactive fibers in the dorsal raphe nucleus
    Wang, Q.-P.; Guan, J.-L.; Ochiai, H.; Nakai, Y.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create folders to
organize your research

Export folders, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off