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Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons.

Gu L, Uhelski ML, Anand S, Romero-Ortega M, Kim YT, Fuchs PN, Mohanty SK - PLoS ONE (2015)

Bottom Line: Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy.Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons.These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

View Article: PubMed Central - PubMed

Affiliation: Biophysics and Physiology Group, Department of Physics, University of Texas at Arlington, Arlington, TX-76019, United States of America.

ABSTRACT
Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

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Behavioral assay of pain inhibition by optogenetic modulation of ACC.(a) Experimental scheme for Formalin test. (b) Optical fiber mounted via cannula in mouse brain (upper panel). Lower panel shows saline or Formalin injection in hind paw. (c) Pain scoring. (d) Pre-formalin pain score of different mice groups, (e) pain score of same groups of mice in post-formalin condition. *P < 0.05 vs. others (transgenic laser off, wild type laser on and wild type laser off). (f) Histogram for comparison of pre and post formalin pain scores for various mice groups at two different time points. *P < 0.05 vs. control (laser off), n = 10 for each group.
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pone.0117746.g003: Behavioral assay of pain inhibition by optogenetic modulation of ACC.(a) Experimental scheme for Formalin test. (b) Optical fiber mounted via cannula in mouse brain (upper panel). Lower panel shows saline or Formalin injection in hind paw. (c) Pain scoring. (d) Pre-formalin pain score of different mice groups, (e) pain score of same groups of mice in post-formalin condition. *P < 0.05 vs. others (transgenic laser off, wild type laser on and wild type laser off). (f) Histogram for comparison of pre and post formalin pain scores for various mice groups at two different time points. *P < 0.05 vs. control (laser off), n = 10 for each group.

Mentions: To evaluate whether or not optogenetic stimulation of inhibitory neurons in the ACC would modulate pain behavior, the formalin test assay of acute inflammatory pain [37] was conducted 1 wk after implantation of the cannula, as shown in Fig. 3A. The formalin test is a widely used tonic model of continuous pain involving neurogenic, inflammatory, and central mechanisms of nociception. Both transgenic and wild type mice were randomly assigned to receive either sham stimulation or laser stimulation. A pre-formalin test was performed (S1 Movie) and involved fiber optic insertion into the guide cannula followed by a subcutaneous injection of normal saline (NS) to the dorsal surface of one hind paw (Fig. 3B). Application of the light stimulus through the optical fiber in pre-formalin tests (S2 Movie) did not lead to any significant behavioral change. Two days after the baseline test, the formalin test was performed in mice that were individually placed into an observation chamber for 45 min. After the formalin injection, the sham (S3 Movie) or light stimulation (S4 Movie) was applied, and the pain response in the form of lifting or licking the injected paw was recorded and scored as shown in Fig. 3C.


Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons.

Gu L, Uhelski ML, Anand S, Romero-Ortega M, Kim YT, Fuchs PN, Mohanty SK - PLoS ONE (2015)

Behavioral assay of pain inhibition by optogenetic modulation of ACC.(a) Experimental scheme for Formalin test. (b) Optical fiber mounted via cannula in mouse brain (upper panel). Lower panel shows saline or Formalin injection in hind paw. (c) Pain scoring. (d) Pre-formalin pain score of different mice groups, (e) pain score of same groups of mice in post-formalin condition. *P < 0.05 vs. others (transgenic laser off, wild type laser on and wild type laser off). (f) Histogram for comparison of pre and post formalin pain scores for various mice groups at two different time points. *P < 0.05 vs. control (laser off), n = 10 for each group.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4340873&req=5

pone.0117746.g003: Behavioral assay of pain inhibition by optogenetic modulation of ACC.(a) Experimental scheme for Formalin test. (b) Optical fiber mounted via cannula in mouse brain (upper panel). Lower panel shows saline or Formalin injection in hind paw. (c) Pain scoring. (d) Pre-formalin pain score of different mice groups, (e) pain score of same groups of mice in post-formalin condition. *P < 0.05 vs. others (transgenic laser off, wild type laser on and wild type laser off). (f) Histogram for comparison of pre and post formalin pain scores for various mice groups at two different time points. *P < 0.05 vs. control (laser off), n = 10 for each group.
Mentions: To evaluate whether or not optogenetic stimulation of inhibitory neurons in the ACC would modulate pain behavior, the formalin test assay of acute inflammatory pain [37] was conducted 1 wk after implantation of the cannula, as shown in Fig. 3A. The formalin test is a widely used tonic model of continuous pain involving neurogenic, inflammatory, and central mechanisms of nociception. Both transgenic and wild type mice were randomly assigned to receive either sham stimulation or laser stimulation. A pre-formalin test was performed (S1 Movie) and involved fiber optic insertion into the guide cannula followed by a subcutaneous injection of normal saline (NS) to the dorsal surface of one hind paw (Fig. 3B). Application of the light stimulus through the optical fiber in pre-formalin tests (S2 Movie) did not lead to any significant behavioral change. Two days after the baseline test, the formalin test was performed in mice that were individually placed into an observation chamber for 45 min. After the formalin injection, the sham (S3 Movie) or light stimulation (S4 Movie) was applied, and the pain response in the form of lifting or licking the injected paw was recorded and scored as shown in Fig. 3C.

Bottom Line: Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy.Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons.These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

View Article: PubMed Central - PubMed

Affiliation: Biophysics and Physiology Group, Department of Physics, University of Texas at Arlington, Arlington, TX-76019, United States of America.

ABSTRACT
Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

Show MeSH
Related in: MedlinePlus