Abstract
Muscarinic acetylcholine receptors (mAChRs) have been widely reported as pharmacological targets for the treatment of pain. However, most of these efforts have focused on CNS mAChRs and their role in modulating nociception at the level of the spinal cord. The present study examines the contribution of peripheral mAChRs in trigeminal nociceptive pathways using a combination of in vivo and in vitro approaches. In the formalin model of orofacial nociception in rats, a peri-oral co-injection of the M2 agonist arecaidine dose-dependently inhibited phase 2 nocifensive behavior up to approximately 50% at 5nmol. This effect was blocked by co-treatment with the mAChR antagonist atropine and was not seen when arecaidine was administered under the skin of the back, a site distant from that of the formalin injection. In vitro superfusion of isolated rat buccal mucosa with the non-selective mAChR agonist muscarine or arecaidine led to a concentration-dependent inhibition of capsaicin-evoked CGRP release to 39% (EC50=255nM) and 28% (EC50=847nM) of control values, respectively. Both responses were blocked by the non-selective mAChR antagonist atropine or the M2 antagonist gallamine. Further, the endogenous ligand ACh produced a bi-phasic response, potentiating evoked CGRP release to 195% of control (EC50=918nM) and inhibiting evoked CGRP release to 45% of control (EC50=255 μM), effects that were shown to be mediated by nAChRs and mAChRs, respectively. Finally, combined in situ hybridization/ immunofluorescence demonstrated that m2 mRNA was present in 20% of trigeminal ganglion neurons between 30 and 60 μm in diameter and that 5-9% of these also expressed CGRP or VR1 immunoreactivity. These results show that activation of peripheral M2 receptors produces antinociception in vivo and the inhibition of nociceptor activity in vitro. While histological analyses at the level of the trigeminal neuronal cell bodies leave open the question of whether the effects of M2 agonists are direct or indirect, these data indicate that primary sensory neuronal M2 receptors may represent a viable peripheral target for the treatment of pain and inflammation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 22-32 |
| Number of pages | 11 |
| Journal | Pain |
| Volume | 107 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - Jan 2004 |
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Keywords
- Capsaicin
- Formalin
- Inflammation
- Muscarinic receptor
- Nociception
- Sensory neuron
ASJC Scopus subject areas
- Clinical Neurology
- Psychiatry and Mental health
- Neurology
- Neuroscience(all)
- Pharmacology
- Clinical Psychology
Cite this
Cholinergic modulation of nociceptive responses in vivo and neuropeptide release in vitro at the level of the primary sensory neuron. / Dussor, Gregory O.; Helesic, Gabriela; Hargreaves, Kenneth M; Flores, Christopher M.
In: Pain, Vol. 107, No. 1-2, 01.2004, p. 22-32.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cholinergic modulation of nociceptive responses in vivo and neuropeptide release in vitro at the level of the primary sensory neuron
AU - Dussor, Gregory O.
AU - Helesic, Gabriela
AU - Hargreaves, Kenneth M
AU - Flores, Christopher M.
PY - 2004/1
Y1 - 2004/1
N2 - Muscarinic acetylcholine receptors (mAChRs) have been widely reported as pharmacological targets for the treatment of pain. However, most of these efforts have focused on CNS mAChRs and their role in modulating nociception at the level of the spinal cord. The present study examines the contribution of peripheral mAChRs in trigeminal nociceptive pathways using a combination of in vivo and in vitro approaches. In the formalin model of orofacial nociception in rats, a peri-oral co-injection of the M2 agonist arecaidine dose-dependently inhibited phase 2 nocifensive behavior up to approximately 50% at 5nmol. This effect was blocked by co-treatment with the mAChR antagonist atropine and was not seen when arecaidine was administered under the skin of the back, a site distant from that of the formalin injection. In vitro superfusion of isolated rat buccal mucosa with the non-selective mAChR agonist muscarine or arecaidine led to a concentration-dependent inhibition of capsaicin-evoked CGRP release to 39% (EC50=255nM) and 28% (EC50=847nM) of control values, respectively. Both responses were blocked by the non-selective mAChR antagonist atropine or the M2 antagonist gallamine. Further, the endogenous ligand ACh produced a bi-phasic response, potentiating evoked CGRP release to 195% of control (EC50=918nM) and inhibiting evoked CGRP release to 45% of control (EC50=255 μM), effects that were shown to be mediated by nAChRs and mAChRs, respectively. Finally, combined in situ hybridization/ immunofluorescence demonstrated that m2 mRNA was present in 20% of trigeminal ganglion neurons between 30 and 60 μm in diameter and that 5-9% of these also expressed CGRP or VR1 immunoreactivity. These results show that activation of peripheral M2 receptors produces antinociception in vivo and the inhibition of nociceptor activity in vitro. While histological analyses at the level of the trigeminal neuronal cell bodies leave open the question of whether the effects of M2 agonists are direct or indirect, these data indicate that primary sensory neuronal M2 receptors may represent a viable peripheral target for the treatment of pain and inflammation.
AB - Muscarinic acetylcholine receptors (mAChRs) have been widely reported as pharmacological targets for the treatment of pain. However, most of these efforts have focused on CNS mAChRs and their role in modulating nociception at the level of the spinal cord. The present study examines the contribution of peripheral mAChRs in trigeminal nociceptive pathways using a combination of in vivo and in vitro approaches. In the formalin model of orofacial nociception in rats, a peri-oral co-injection of the M2 agonist arecaidine dose-dependently inhibited phase 2 nocifensive behavior up to approximately 50% at 5nmol. This effect was blocked by co-treatment with the mAChR antagonist atropine and was not seen when arecaidine was administered under the skin of the back, a site distant from that of the formalin injection. In vitro superfusion of isolated rat buccal mucosa with the non-selective mAChR agonist muscarine or arecaidine led to a concentration-dependent inhibition of capsaicin-evoked CGRP release to 39% (EC50=255nM) and 28% (EC50=847nM) of control values, respectively. Both responses were blocked by the non-selective mAChR antagonist atropine or the M2 antagonist gallamine. Further, the endogenous ligand ACh produced a bi-phasic response, potentiating evoked CGRP release to 195% of control (EC50=918nM) and inhibiting evoked CGRP release to 45% of control (EC50=255 μM), effects that were shown to be mediated by nAChRs and mAChRs, respectively. Finally, combined in situ hybridization/ immunofluorescence demonstrated that m2 mRNA was present in 20% of trigeminal ganglion neurons between 30 and 60 μm in diameter and that 5-9% of these also expressed CGRP or VR1 immunoreactivity. These results show that activation of peripheral M2 receptors produces antinociception in vivo and the inhibition of nociceptor activity in vitro. While histological analyses at the level of the trigeminal neuronal cell bodies leave open the question of whether the effects of M2 agonists are direct or indirect, these data indicate that primary sensory neuronal M2 receptors may represent a viable peripheral target for the treatment of pain and inflammation.
KW - Capsaicin
KW - Formalin
KW - Inflammation
KW - Muscarinic receptor
KW - Nociception
KW - Sensory neuron
UR - http://www.scopus.com/inward/record.url?scp=0346724925&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0346724925&partnerID=8YFLogxK
U2 - 10.1016/j.pain.2003.09.022
DO - 10.1016/j.pain.2003.09.022
M3 - Article
C2 - 14715385
AN - SCOPUS:0346724925
VL - 107
SP - 22
EP - 32
JO - Pain
JF - Pain
SN - 0304-3959
IS - 1-2
ER -