An NK1 receptor antagonist microinjected into the periaqueductal gray blocks lateral hypothalamic-induced antinociception in rats.

Substantial data are accumulating that implicate the lateral hypothalamus (LH) as part of the descending pain modulatory system. The LH modifies nociception in the spinal cord dorsal horn partly through connections with the periaqueductal gray (PAG), an area known to play a central role in brainstem modulation of nociception. Early work demonstrated a putative substance P connection between the LH and the PAG, but the connection is not fully defined. To determine whether LH-induced antinociception mediated by the PAG is neurokinin1 (NK1) receptor-dependent, we conducted behavioral experiments in which the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of lightly anesthetized female Sprague-Dawley rats (250-350 g) and antinociception was obtained on the tail flick or foot withdrawal tests. Cobalt chloride (100 nM), which reversibly blocks synaptic activation, blocked LH-induced antinociception. In another set of experiments, the specific NK1 receptor antagonist L-703,606 (5 microg) was microinjected in the PAG following LH stimulation with carbachol abolished LH-induced antinociception as well. Microinjection of cobalt chloride or L-703,606 in the absence of LH stimulation had no effect. These behavioral experiments coupled with earlier work provide converging evidence to support the hypothesis that antinociception produced by activating neurons in the LH is mediated in part by the subsequent activation of neurons in the PAG by NK1 receptors.

Lateral hypothalamic-induced antinociception may be mediated by a substance P connection with the rostral ventromedial medulla.

Stimulation of the lateral hypothalamus (LH) produces antinociception modified by intrathecal serotonergic receptor antagonists. Spinally-projecting serotonergic neurons in the LH have not been identified, suggesting that the LH innervates brainstem serotonergic neurons in the rostral ventromedial medulla (RVM), known to modify nociception in the spinal cord dorsal horn. To determine whether substance P (SP) plays a role in LH-induced antinociception mediated by the RVM, we conducted an anatomical experiment using retrograde tract tracing combined with double label immunocytochemistry and found that neuron profiles immunoreactive for SP in the LH project to the RVM. To further identify a functional connection between SP neurons in the LH and the RVM, the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of female Sprague-Dawley rats (250-350 g) and antinociception was obtained on the tail flick or foot withdrawal tests. Cobalt chloride (100 nM) was then microinjected in the RVM to block synaptic activation of spinally-projecting RVM neurons. Within 5 min of the cobalt chloride injection, the antinociceptive effect of carbachol stimulation was blocked. In another set of experiments, the specific NK1 receptor antagonist L-703,606 (5 microg) was microinjected in the RVM following LH stimulation with carbachol and abolished LH-induced antinociception as well. Microinjection of cobalt chloride or L-703,606 in the absence of LH stimulation had no effect. These anatomical and behavioral experiments provide converging evidence to support the hypothesis that antinociception produced by activating neurons in the LH is mediated in part by the subsequent activation of spinally-projecting neurons in the RVM.

The challenge of chronic pain.

Chronic pain is a complex problem with staggering negative health and economic consequences. The complexity of chronic pain is presented within Cervero and Laird's model that describes three phases of pain, including pain without tissue damage, pain with tissue damage and inflammation, and neuropathic pain. The increased afferent input in phases 2 and 3 of chronic pain produces marked changes in primary afferents, dorsal root ganglia, and spinal cord dorsal horn. These changes promote the symptoms of chronic pain, including spontaneous pain, hyperalgesia, and allodynia. Increased afferent input also evokes supraspinal input to the dorsal horn, including biphasic innervation from the ventromedial medulla and A7 catecholamine cell group, that promotes hyperalgesia and allodynia. More rostral brain structures, such as the lateral hypothalamus, amygdala, and hippocampus, may also play a role in chronic pain. Although much has been discovered about the multiple pathological mechanisms involved in chronic pain, further research is needed to fully comprehend these mechanisms.