Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar9,Met(O2)11]-substance P-saporin: behavioral and anatomical analyses.
Lumbar intrathecal injections of substance P-saporin (SP-sap) destroy dorsal horn neurons that express the neurokinin-1 receptor (NK-1R) resulting in decreased responses to a range of noxious stimuli and decreased hyperalgesia and allodynia. Forebrain injections of SP-sap produce considerable non-specific damage raising some concern about use of this toxin in vivo. The more stable and selective substance P congener, [Sar9,Met(O2)11]substance P coupled to saporin (SSP-sap) produces much more selective forebrain lesions at significantly lower doses. The present study sought to determine the anatomic and nocifensive behavioral effects of lumbar intrathecal injections of the more precisely targeted SSP-sap. On the basis of loss of lamina I NK-1R staining, lumbar intrathecal SSP-sap was seven times more potent than SP-sap and produced no loss of NK-1R expressing neurons in deeper laminae (III-VI or X). Transient decreases in hotplate responding occurred at 44 degrees C and 47 degrees C but not 52 degrees C during the first 3 weeks after SSP-sap injection with return to baseline by 4 weeks. Operant escape responses were reduced at 0.3 degrees C, 44 degrees C and 47 degrees C for at least 4 months. In the formalin test, SSP-sap also was about seven times more potent than SP-sap in reducing phase two behavior in both female Long Evans and male Sprague-Dawley rats. Both SSP-sap and SP-sap reduced formalin-induced FOS expression in deep and superficial laminae of the L4 dorsal horn in parallel with the reduction in phase 2 behavior. In summary, SSP-sap is highly effective in destroying lamina I NK-1R expressing neurons, without loss of deep NK-1R neurons. The behavioral effects of SSP-sap are similar to SP-sap suggesting that the antinociceptive effects of both toxins are indeed due to selective loss of NK-1R neurons in lamina I. SSP-sap is an attractive agent for possible treatment of chronic pain.
Wiley
R G
RG
Laboratory of Experimental Neurology, VA TVHS, Nashville, TN 37212-2637, USA. ronald.wiley@vanderbilt.edu
Kline
R H
RH
Vierck
C J
CJ
D000700:Analgesics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004924:Escape Reaction / Q000187:drug effects; D005260:Female; D005557:Formaldehyde; D016762:Genes, fos / Q000187:drug effects; D006358:Hot Temperature; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins
D000700:Analgesics; D018040:Receptors, Neurokinin-1; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C454685:SSP-SAP fusion protein, recombinant; D005557:Formaldehyde; D000076985:Saporins