Co-localization of p-CREB and p-NR1 in spinothalamic neurons in a chronic muscle pain model

Abstract

Activation of the cAMP pathway is an important mediator of chronic muscle pain. This study examined phosphorylation of the transcription factor cAMP-response-element-binding protein (p-CREB) and the NR1 subunit of the NMDA receptor (p-NR1) in the spinal cord. Bilateral mechanical hyperalgesia of the paw was induced by administering two injections of acidic saline, 5 d apart, into the gastrocnemius muscle of male Sprague Dawley rats. The proportion of spinothalamic neurons that expressed p-NR1 or p-CREB did not change in the dorsal horn 24 hours after the second intramuscular acid injection compared with animals that received pH 7.2 injections. This lack of change in spinothalamic neurons in the dorsal horn may be due to increases in individual spinothalamic neurons or increases in non-spinothalamic neurons. There was an increase in the proportion of spinothalamic neurons expressing p-NR1 in lamina X. These findings suggest that there are region-specific changes in spinothalamic neurons that express p-NR1 and lamina X may play an important role in the modulation of chronic muscle pain.

Injection of adjuvant but not acidic saline into craniofacial muscle evokes nociceptive behaviors and neuropeptide expression

“…Despite the presence of functional ASIC3 channels on these neurons, we failed to detect any behavioral changes following repeated injections of acidic saline into the masseter muscle. These results indicate that either ASIC3 receptors are not activated during injection of acidic saline into craniofacial muscle or ASIC3 activation does not cause long-term neuronal changes and central sensitization in the brainstem as occurs in the spinal cord (Skyba et al, 2002;Sluka et al, 2002;Bement and Sluka, 2007;Yokoyama et al, 2007).…”

“…In spite of their prevalence, the pathophysiological mechanisms of these disorders are poorly understood. Since the central mechanisms of craniofacial pain may differ from those of spinal regions (Bereiter et al, 2000), it is important to investigate chronic pain mechanisms specific to the craniofacial region.Mechanisms of hindlimb muscle nociception have been investigated using an animal model in which acidic saline is injected repeatedly into hindlimb muscles Skyba et al, 2002;Sluka et al, 2002;Sluka et al, 2003;Hoeger-Bement and Sluka, 2003;Nielsen et al, 2004;Bement and Sluka, 2007;Yokoyama et al, 2007). Intramuscular injection of acidic saline into the hind limb muscle of rodents evokes central sensitization and long-lasting reductions in paw withdrawal thresholds Skyba et al, 2002).…”

Resident Macrophages in Muscle Contribute to Development of Hyperalgesia in a Mouse Model of Noninflammatory Muscle Pain

“…Specifically, there is sensitization of neurons in the spinal cord and the rostral ventromedial medulla (RVM) contributes to both the development and maintenance of hyperalgesia after repeated acid injection [52;54]. After the second acid saline injection, both spinally and supraspinally, there is an increase in release of glutamate [43;49], increase in phosphorylation of the N-methyl-d-aspartate (NMDA) receptor [5;51], and blockade or downregulation of NMDA receptors attenuates the development of hyperalgesia [8;9;48]. Thus, central mechanisms are also involved in the development of chronic muscle pain and thus a combination of both peripheral and central factors are critical to the full manifestation of the pain-behaviors in this chronic muscle pain model.…”

Spinal Cord Stimulation Reduces Mechanical Hyperalgesia and Restores Physical Activity Levels in Animals with Noninflammatory Muscle Pain in a Frequency-Dependent Manner

“…62,63 However, once developed, the hyperalgesia is independent of nociceptor activity, presents with minimal tissue damage, shows sensitization of dorsal horn neurons, and requires activation of central pathways to maintain the hyperalgesia. 59,[62][63][64][65][66] Thus, the model mimics the signs and symptoms of fibromyalgia. The hyperalgesia in this model also responds with a similar pharmacological and nonpharmacological treatment profile to fibromyalgia.…”