title: Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia.
abstract: It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1Rs) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar(9),Met(O2)(11)-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. Rats received injections of SSP-SAP (1 μM) or an equal volume of 1 μM of saporin conjugated to artificial peptide (Blank-SAP). Stereological analysis of NK-1R- and NeuN-labeled neurons in the RVM was determined 21-24 days after treatment. Withdrawal responses to mechanical and heat stimuli applied to the plantar hindpaw were determined 5-28 days after treatment. Withdrawal responses were also determined before and after intraplantar injection of capsaicin (acute hyperalgesia) or complete Freund's adjuvant (CFA) (prolonged hyperalgesia). The proportion of NK-1R-labeled neurons in the RVM was 8.8 ± 1.3% in naïve rats and 8.1 ± 0.8% in rats treated with Blank-SAP. However, injection of SSP-SAP into the RVM resulted in a 90% decrease in NK-1R-labeled neurons. SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP. These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in modulating acute pain or morphine analgesia, but rather are involved in pain facilitation and the development and maintenance of hyperalgesia.
authors.affiliation: Department of Diagnostic & Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Khasabov
authors.forename: D A
authors.initials: DA
authors.lastname: Simone
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002211:Capsaicin; D002404:Catheterization; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology* / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism* / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D018040:Receptors, Neurokinin-1; D009020:Morphine; D002211:Capsaicin
keywords: ANOVA; CCK; CFA; N-methyl-d-aspartate; NDS; NK-1R; NK-1R-immunoreactive; NK-1R-ir; NMDA; NeuN-immunoreactive; NeuN-ir; ON cells; PBS; RVM; SAP; SP; SSP; Sar(9),Met(O(2))(11)-Substance P; analysis of variance; capsaicin; cholecystokinin; complete Freund’s adjuvant; descending facilitation; inflammation; neurokinin-1 receptor; normal donkey serum; pain modulation; phosphate-buffered saline; rostral ventromedial medulla; saporin; substance P