Stacey C. LaGraize

Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain.

Various limbic system structures have been implicated in processing noxious information. One such structure is the anterior cingulate cortex (ACC), a region that is thought to modulate higher order processing of noxious input related to the affective/motivational component of pain. The present experiment examined the involvement of the ACC in higher order pain processing by measuring paw withdrawal threshold and escape/avoidance responses in the L5 spinal nerve ligation model of neuropathic pain before and following electrolytic lesion of the ACC. In the place/escape avoidance paradigm, the afflicted paw is mechanically stimulated when the animal is in the preferred dark area of the chamber and the contralateral paw is stimulated when the animal is in the light area. Escape/avoidance was defined as a shift from the preferred dark area to an increase of time spent in the light area of the chamber. Animals with L5 ligation had significantly lower mechanical paw withdrawal threshold (hypersensitivity) and enhanced escape/avoidance behavior. ACC lesion in animals with L5 ligation did not alter mechanical hypersensitivity, but did significantly decrease escape/avoidance behavior. Anxiety, as measured using the light-enhanced startle paradigm, was not altered by ACC lesion. These results highlight the utility of novel behavioral test paradigms and provide additional support for the role of the ACC in higher order processing of noxious information, suggesting that ACC lesions selectively decrease negative affect associated with neuropathy-induced hypersensitivity.

Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats

The present study investigated the effect of lesions of the anterior cingulate cortex (ACC) on mechanical allodynia/hyperalgesia after L5 ligation or on inflammatory nociceptive responses following formalin injection in the rat. For both the neuropathic and inflammatory pain models, three groups of animals were used. The control groups consisted of a group of sham lesioned animals and a group of animals that had unilateral damage to the ACC or unilateral/bilateral damage to surrounding cortical tissue. The third group consisted of animals that had at least 75% bilateral damage of the ACC. Subjects received L5 ligation or a 0.05-ml injection of 1% formalin into the plantar surface of the hindpaw. In contrast to the control groups, bilateral ACC lesions significantly decreased inflammatory nociceptive responses during the prolonged, tonic portion of the formalin test (20-35 min). The difference between the groups was most prevalent in the amount of time spent licking the paw. However, ACC lesions did not significantly attenuate the enhanced mechanical paw withdrawal threshold in the neuropathic nociceptive model. These results suggest a differential role of the ACC in the modulation of different types of pain conditions.

Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system

Morphine and surgical cingulotomy, or transection of the anterior cingulate cortex (ACC), provides relief of chronic pain by selectively decreasing the affective dimension of the condition without altering sensory processing. Clinical reports suggest that morphine might be acting at the level of the ACC to alter the complex experience of pain. Therefore, the purpose of this experiment was to directly examine the functional role of the ACC in processing the aversive nature of pain induced by ligation of the L5 spinal nerve. Systemic administration of low dose morphine produced a selective attenuation of pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of mechanical paw withdrawal threshold. Supraspinally, microinjection of morphine into the ACC produced a selective naloxone reversible reduction in pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of response to mechanical stimulation. These data demonstrate the central role of the ACC opioid system in selectively processing the aversive quality of noxious mechanical stimulation in animals with a persistent pain condition.

GABAA but not GABAB receptors in the rostral anterior cingulate cortex selectively modulate pain-induced escape/avoidance behavior

The rostral anterior cingulate cortex (rACC) is involved in supraspinal nociceptive processing. ACC lesions relieve persistent pain, but do not affect the patients ability to localize a noxious stimulus. Since the rACC has a high density of GABA receptors, it is possible that pain processing is influenced by these receptors in the rACC. The present experiments examined the involvement of rat rACC GABA(A) and GABA(B) receptors in regard to sensitivity to mechanical stimulation and escape/avoidance behavior in response to a noxious stimulus following L5 spinal nerve ligation. Rats were or were not afflicted with a neuropathic pain condition by an L5 spinal nerve ligation. rACC microinjection of 10 microg/microl GABA, a GABA(A) agonist (0.001 microg/microl, 0.1 microg/microl, or 0.5 microg/microl muscimol), a GABA(B) agonist (0.1 microg/microl, 1 microg/microl, or 5 microg/microl baclofen), or saline, did not alter mechanical withdrawal thresholds. Importantly, following 10 microg/microl GABA, 0.1 microg/microl, or 0.5 microg/microl muscimol microinjected into the rACC, place escape/avoidance behavior to a noxious mechanical stimulus was attenuated in injured animals. The attenuation was specific to the rACC and was blocked by a preadministered microinjection of the appropriate antagonist(s) into the rACC. In conclusion, microinjection of GABA and higher doses of muscimol did not decrease mechanical hyperalgesia but did attenuate place escape/avoidance behavior that is associated with mechanical stimulation of the ligated paw. These results provide additional support for the role of the rACC in higher order supraspinal processing of noxious events and suggest that rACC GABA(A) receptors significantly contribute to this processing.

Electrical stimulation of the primary somatosensory cortex inhibits spinal dorsal horn neuron activity

Cortical stimulation has been demonstrated to alleviate certain pain conditions. The aim of this study was to determine the responses of the spinal cord dorsal horn neurons to stimulation of the primary somatosensory cortex (SSC). We hypothesized that direct stimulation of the SSC will inhibit the activity of spinal dorsal horn neurons by activating the descending inhibitory system. Thirty-four wide dynamic range spinal dorsal horn neurons were recorded in response to graded mechanical stimulation (brush, pressure, and pinch) at their respective receptive fields while a stepwise electrical stimulation (300 Hz, 0.1 ms, at 10, 20, and 30 V) was applied in the SSC through a bipolar tungsten electrode. The responses to brush at control, 10 V, 20 V, 30 V, and recovery were 16.0 +/- 2.3, 15.8 +/- 2.2, 14.6 +/- 1.8, 14.8 +/- 2.0, and 17.0 +/- 2.2 spikes/s, respectively. The responses to pressure at control, 10 V, 20 V, 30 V, and recovery were 44.7 +/- 5.5, 37.0 +/- 5.6, 29.5 +/- 4.8, 31.6 +/- 5.2, and 43.2 +/- 5.7 spikes/s, respectively. The responses to pinch at control, 10 V, 20 V, 30 V, and recovery were 58.1 +/- 7.0, 42.9 +/- 5.5, 34.8 +/- 3.9, 34.6 +/- 4.4, and 52.6 +/- 6.0 spikes/s, respectively. Significant decreases of the dorsal horn neuronal responses to pressure and pinch were observed during SSC stimulation. It is concluded that electrical stimulation of the SSC produces transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting innocuous stimuli.

Dorsal horn neuron response patterns to graded heat stimuli in the rat.

Sensory input from various receptors in the periphery first becomes integrated in the spinal cord dorsal horn. The response of the spinal cord dorsal horn neurons to mechanical stimuli are classified as low threshold, high threshold, and wide dynamic range neurons. However, the response pattern of deep dorsal horn cells to heat has not been well described. In this study, the response of the spinal cord dorsal horn neurons to graded heat stimuli were characterized in 147 neurons in rats by extracellular single cell recording. After a differentiable cell was identified, the Peltier heat stimulator was applied to the receptive field and the base temperature was set at 30 degrees C. The heat stimulus was delivered for 10 s from 37-51 degrees C in 2 degrees C increments, with an inter-stimulus interval of 30 s. Out of the 147 neurons, five statistically distinguishable response patterns were identified by latent class cluster analysis. It is concluded that variation of temperature may account for the observed results and indicate functionally different subsets of heat-responsive cells in the deep dorsal horn.

Effect of chronic vincristine treatment on mechanical withdrawal response and pre-pulse inhibition in the rat

Chemotherapeutic agents are associated with a number of serious side-effects. In addition to the development of peripheral neuropathy, patients often complain of additional symptoms related to attentional mechanisms. Although a great deal of interest is directed towards understanding the mechanisms underlying the development of peripheral neuropathy, there is a paucity of research that has examined the extent of impairment of attention in animals receiving chemotherapeutic agents. Therefore, the purpose of this experiment was to examine attentional mechanisms using the method of pre-pulse inhibition in animals that were chronically treated with vincristine. Although vincristine treated animals developed signs of peripheral neuropathy, there was no associated alteration of pre-pulse inhibition relative to vehicle treated animals. These results highlight the importance of continuing to develop methodology to model symptom burden in patients receiving chemotherapy.

Decreased L5 spinal nerve ligation nociceptive behavior following L4 spinal nerve transection.

This study used the escape/avoidance paradigm to explore the role of the L4 spinal nerve in L5 ligation nociception. Unlike L5-ligated controls, L5-ligated/L4-transected animals had normal mechanical withdrawal threshold and did not escape/avoid mechanical stimulation of the afflicted paw. The result from the escape/avoidance paradigm, which does not rely on a reflexive withdrawal response, directly supports the hypothesis that the L4 spinal nerve contributes to L5 ligation neuropathic pain.