Pain mechanismInhibitory M2 muscarinic receptors are upregulated in both axotomized and intact small diameter dorsal root ganglion cells after peripheral nerve injury
Section snippets
Animals
Male Sprague–Dawley rats (Harlan Industries, Indianapolis, IN, USA), weighing 200–250 g, were used in this study. Animal surgery was confirmed with the Wake Forest University Guidelines on the ethical use of animals, and studies were performed under Animal Care and Use Committee approval. All experiments conformed with guidelines regarding the study of animals published by the International Association for the Study of Pain, including minimizing the number of animals studied and their
General observations and response to potassium stimulation
The L5 and L6 spinal nerve ligation strongly decreased the withdrawal threshold of the hindpaw ipsilateral to ligation from 40±4.1 g to 1.9±0.2 g (P<0.001, n=27). The withdrawal threshold in the contralateral hindpaw was also significantly decreased (P<0.001) in accordance with previous reports (Kim and Chung, 1992). Withdrawal threshold in the contralateral hindpaw (14±1.9 g) was nonetheless higher than our criterion for hypersensitivity (<4 g), and significantly higher than that of the paw
Discussion
This study utilized a nonspecific membrane depolarizing stimulus (KCl) to survey the populations of small- and medium-sized DRG neurons which were inhibited by bethanechol in normal animals and DRG neurons which were axotomized as well as their uninjured neighbors after spinal nerve ligation. Two key findings were observed: that the pharmacology and immunohistochemistry was consistent with inhibitory M2 mAChRs on these neurons in normal animals, and that the proportion of small to medium size
Conclusion
In summary, the current study, utilizing a functional and immunologic definition, supports the presence of inhibitory M2 mAChRs on sensory neurons and for the first time to our knowledge, demonstrates upregulation of these inhibitory receptors in uninjured DRG neurons whose axons intermingle with injured afferents following peripheral nerve injury. Increase in M2 AChR immunoreactivity and function but decreased TRPV1 agonist response following nerve injury argues that these proteins are
Acknowledgments
This work was supported in part by NIH grants GM35523 and NS42386.
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