Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain

Abstract

No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right non-ligated paws (p < 0.05). Rats were given carbachol in the LH followed by intrathecal injection of the orexin-1 receptor (OX1) antagonist SB-334867, which blocked LH-induced antinociception compared to control groups (p < 0.05) in the left paw, but not in the right paw. These findings support the hypothesis that LH stimulation produces antinociception in rats with thermal hyperalgesia from neuropathic pain via an orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

Reduced GABAergic neuronal activity in zona incerta causes neuropathic pain in a rat sciatic nerve chronic constriction injury model

“…Many previous studies report links between the ZI and chronic pain 19,20. The ZI is a GABAergic nucleus located in the ventral thalamus, which is a subdivision of the diencephalon, and most ZI neurons are GABAergic 21,22.…”

Anatomical evidence for lateral hypothalamic innervation of the pontine A7 catecholamine cell group in rat

“…Noradrenergic neurons in the A7 area increase their firing rates when exposed to substance P [21], microinjection of substance P in the A7 area produces antinociception [6], and microinjection of the neurokinin1 receptor antagonist, L-703,606, into the A7 area reduces LH-induced antinociception [13]. Orexins-containing neurons are prevalent in the LH and are known to play a role in nociceptive modulation either by a direct connection to the spinal cord dorsal horn or at supraspinal levels [22,23,24]. LH orexin-containing neurons project to the parabrachial area [25], but no behavioral studies have been done demonstrating an LH to A7 orexins connection.…”

“…This study focused on the actions of LH neurons only in the noradrenergic descending modulatory system. As mentioned earlier, LH stimulation also activates orexin–containing neurons in the LH that project directly to the dorsal horn [24,25], and possibly met-enkephalin [27] and glutamate neurons [28]. Similarly, LH innervation of the A7 area may activate non- noradrenergic neurons, including GABA and glycine neurons that are known to exist near the A7 cells [7,21].…”

Mechanisms, Predictors, and Challenges in Assessing and Managing Painful Chemotherapy-Induced Peripheral Neuropathy

“…26,60,61 Central sensitization may also result from direct chemotoxic damage [62][63][64] and/or dysfunction of the CNS descending pain-modulating pathways. [65][66][67][68] Very few studies have reported chemotherapy effects on descending pain-modulating pathways; however, emerging evidence suggests that analgesia through the descending pain-modulating pathway, particularly involving the lateral hypothalamus and orexinergic system, may be key in combatting CIPN pain. [65][66][67][68] The longer CIPN goes unmanaged, the more central sensitization progresses; painful CIPN then becomes chronic.…”