The anterior cingulate cortex and pain processing

Abstract

The neural network that contributes to the suffering which accompanies persistent pain states involves a number of brain regions. Of primary interest is the contribution of the cingulate cortex in processing the affective component of pain. The purpose of this review is to summarize recent data obtained using novel behavioral paradigms in animals based on measuring escape and/or avoidance of a noxious stimulus. These paradigms have successfully been used to study the nature of the neuroanatomical and neurochemical contributions of the anterior cingulate cortex (ACC) to higher order pain processing in rodents.

Keywords: anterior cingulate cortex; pain; pain affect; place avoidance; place escape.

Figure 1

Percentage of time (mean ± SEM) for each 5 min test interval spent in the light side of the test chamber for animals following peripheral nerve damage (L5 ligation, A) or inflammation (subcutaneous complete Freund’s adjuvant (CFA), B). When mechanical stimulation of the ligated or inflamed paw was associated with the preferred dark area of the chamber animals spend more time in the light area of the chamber indicating that the animals find stimulation of the hypersensitive paw aversive (Reprint from LaBuda and Fuchs, 2000a).

Figure 2

Mechanical Paw Withdrawal Threshold. (A) Mean ± SEM mechanical paw withdrawal threshold prior to stereotaxic surgery for sham ACC, dorsal/unilateral ACC lesion, or bilateral ACC lesion for animals with sham ligation or ligation of the L5 spinal nerve. (B) Mean ± SEM mechanical paw withdrawal threshold following stereotaxic surgery for sham ACC, dorsal/unilateral ACC lesion, or bilateral ACC lesion for animals with sham ligation or ligation of the L5 spinal nerve. *** p < 0.001 versus right paw control; ^# p < 0.001 versus sham ACC lesion ligated paw; p < 0.01 versus sham ACC lesion ligated paw. Place Escape/Avoidance Behavior. (C) Mean ± SEM percentage of time within the light side of the test chamber prior to stereotaxic surgery for sham ACC, dorsal/unilateral ACC lesion, or bilateral ACC lesion for animals with sham ligation or ligation of the L5 spinal nerve. (D) Mean ± SEM percentage of time within the light side of the test chamber following stereotaxic surgery for sham ACC, dorsal/unilateral ACC lesion, or bilateral ACC lesion for animals with sham ligation or ligation of the L5 spinal nerve. * p < 0.05 versus sham ACC lesion ligation control (Reprint from LaGraize et al., 2004b).

Figure 3

Summary of ACC modulation of spinal dorsal horn neuronal responses. The site of stimulating electrode was verified by brain histology. The arrow points to the anterior cingulate cortex (Cg1) on the left according to the coordinates provided by Paxinos and Watson (1998) on the right. Responses of spinal dorsal horn (DH) neurons to mechanical stimuli (Brush, Pressure, and Pinch) during ACC stimulation. The results are combined for ipsilateral and contralateral ACC stimulation. *** p < 0.001 (Modified from Senapati et al., ; with permission).

Figure 4

(A) Mean (± SEM) time spent in the light side of the PEAP chamber in sham vlPAG lesioned animals. L5 SNL, Sham ACC stimulated animals avoided noxious hindpaw stimulation significantly more than sham ligated, sham ACC stimulated animals. ACC stimulation did not have an effect in sham ligated animals, but significantly attenuated the avoidance behavioral response in L5 SNL animals. * p < 0.05 compared to sham ligated + sham ACC stimulation treated animals. (B) Mean (± SEM) time spent in the light side of the PEAP chamber in L5 SNL animals with vlPAG lesions or incomplete vlPAG lesions. L5 SNL, Sham ACC stimulated animals with an incomplete lesion of the vlPAG avoided noxious hindpaw stimulation significantly more than L5 SNL, ACC stimulated animals with an incomplete vlPAG lesion. There was not a significant avoidance response following vlPAG lesions in ACC stimulated, L5 SNL animals. * p < 0.05 compared to sham ligated + sham ACC stimulation treated animals (Reprint from LaBuda and Fuchs, 2005).

Figure 5

Systemic Morphine. (A) Mean ± SEM mechanical paw withdrawal threshold difference scores (left paw–right paw) prior to and following drug administration (Saline, 0.5 mg/kg morphine, 1.0 mg/kg morphine) for animals with sham ligation or ligation of the L5 spinal nerve. (B) Mean ± SEM percentage of time within the light side of the test chamber for the duration of the 30-min test period following drug administration (Saline, 0.5 mg/kg morphine, 1.0 mg/kg morphine) for animals with sham ligation or ligation of the L5 spinal nerve. * p < 0.05 versus Ligation/saline at that time point; ** p < 0.01 versus Ligation/saline at that time point; *** p < 0.001 versus Ligation/saline at that time point; ^### p < 0.001 versus same group at pre-injection time point. (C) Mean ± SEM mechanical paw withdrawal threshold difference scores (left paw–right paw) prior to and following microinjection (Saline, 20 µg/µl morphine) into the ACC for animals with sham ligation or ligation of the L5 spinal nerve. (D) Mean ± SEM percentage of time within the light side of the test chamber for the duration of the 30-min test period following microinjection (Saline, 20 µg/µl morphine) into the ACC for animals with sham ligation or ligation of the L5 spinal nerve. * p < 0.05 versus Ligation/saline; ** p < 0.01 versus Ligation/saline; *** p < 0.001 versus Ligation/saline (Reprint from LaGraize et al., 2006).