Attenuation of cannabinoid-induced inhibition of medullary dorsal horn neurons by a kappa-opioid receptor antagonist

Abstract

The kappa-opioid receptor (KOR) antagonist norbinaltorphimine (nor-BNI) attenuates behavioral antinociception produced by spinal administration of the cannabinoid receptor agonist delta-9-tetrahydorcannabinol (THC). The present study examined the ability of nor-BNI to prevent cannabinoid-induced inhibition of medullary dorsal horn (MDH) nociceptive neurons and antinociception produced by the cannabinoid agonist WIN 55,212-2 (WIN-2). Extracellular, single unit recordings of lamina I and lamina V MDH neurons was performed in urethane anesthetized rats. Heat-evoked activity was measured before and after local brainstem application of nor-BNI or vehicle followed by WIN-2. In both lamina I and lamina V neurons, prior application of nor-BNI prevented the inhibition of heat-evoked activity by WIN-2. In separate experiments, the contribution of KOR to cannabinoid-induced increases in heat-evoked head withdrawal latencies was assessed in lightly urethane-anesthetized rats. Antinociception produced by intrathecal administration of WIN-2 and THC was attenuated by prior administration of nor-BNI. In contrast, antinociception produced by the cannabinoid CP55940 remained unaffected by prior administration of nor-BNI. These results indicate that cannabinoid inhibition of nociceptive reflexes produced by WIN-2 and THC may result from inhibition of dorsal horn neurons through a KOR-dependent mechanism.

Development of κ Opioid Receptor Antagonists

“…In contrast, antinociception produced by the nonclassical cannabinoid agonist 6) remained unaffected by prior administration of nor-BNI. 99 Interestingly, nor-BNI also blocked the antinociception produced by spinal administration of THC. 100 Even though the degree of selectivity and potency following systemic administration of these naltrexone-related ligands was limited, the discovery of opioid-selective antagonists for KORs such as nor-BNI and GNTI by Portoghese and collaborators was of major significance in studies of the relationship to function of opioid receptors.…”

“…In contrast, antinociception produced by the non-classical cannabinoid agonist 2-[(1 R ,2 R ,5 R )-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) ( 11 ) (Figure 6) remained unaffected by prior administration of nor-BNI. 99 Interestingly, nor-BNI also blocked the antinociception produced by spinal administration of THC. 100 …”

Systemic Kappa Opioid Receptor Agonists in the Treatment of Chronic Pruritus: A Literature Review

“…In the CNS, KOR are localized in axons in the medial prefrontal cortex (23), in the nucleus accumbens, hypothalamic nuclei, periaqueductal gray (PAG), nucleus of the solitary tract, ventral tegmental area, amygdala, neocortex and supraspinal nucleus (24)(25)(26) and in the dorsal horn ofthe spinal cord (27). Interestingly, in the dorsal horn ofthe spinal cord, KOR may be linked with the cannabinoid system (28). Systemic application of the cannabinoid receptor agonist delta-9-tetrahydorcamiabinol (THC) was demonstrated to inhibit nociceptive reflexes, possibly resulting fi-om an inhibition of dorsal horn neurones through a KORdependent mechanism (28).…”

“…Interestingly, in the dorsal horn ofthe spinal cord, KOR may be linked with the cannabinoid system (28). Systemic application of the cannabinoid receptor agonist delta-9-tetrahydorcamiabinol (THC) was demonstrated to inhibit nociceptive reflexes, possibly resulting fi-om an inhibition of dorsal horn neurones through a KORdependent mechanism (28). KOR-expressing neurones are also located in the dorsal and trigeminal root ganglia (29), which is an important link to the peripheral nervous system.…”

Immunohistochemistry detection of kappa-opioid receptors in human skin

“…В центральной нервной системе КОР локализуются в аксонах и медиальной префронтальной коре [29], в прилежащих ядрах, гипоталамических ядрах, в периакведуктальном сером веществе мозга, ядрах одиночного пучка, вентральной области покрышки, мозжечке, новой коре головного мозга и супраспинальных ядрах [30][31][32] и в задних рогах спинного мозга [33]. примечательно, что в задних рогах спинного мозга КОР могут быть связаны с канна-биоидной системой [34]. Нейроны, экспрессирующие КОР, также расположены у основания дорсальных ганглиев и в ганглиях тройничного нерва [35], которые являются важной связью с периферической нервной системой.…”