Intrathecal coadministration of D-APV and morphine is maximally effective in a rat experimental pancreatitis model.
BACKGROUND
Many studies have demonstrated that either glutamate -methyl-d-aspartate (NMDA) receptor antagonists or opioid receptor agonists provide antinociception. Spinal coadministration of an NMDA receptor antagonist and morphine has an additive action for control of various pain states in animal models. The current study examined spinal coadministration of low doses of NMDA receptor antagonist, D-(-)-2-Amino-5-phosphonovalerate (D-APV), and mu-opioid receptor agonist, morphine sulfate (MS), in reducing visceral nociception using an acute bradykinin induced pancreatitis model in rats.


METHODS
An intrathecal catheter was surgically inserted into the subarachnoid space for spinal drug administration in Sprague-Dawley rats. A laparotomy was performed for ligation and cannulation of the bile-pancreatic duct. Rats were pretreated intrathecally with artificial cerebrospinal fluid (aCSF), D-APV, MS, or combined administration of D-APV and MS. These treatments were given 30 min before noxious visceral stimulation with bradykinin injected through the bile-pancreatic catheter. Spontaneous behavioral activity tests, including cage crossing, rearing, and hind limb extension, were conducted before and after bradykinin injection into the bile-pancreatic duct to assess visceral nociception.


RESULTS
Spinal pretreatment of D-APV or low doses of MS partially reduced visceral pain behaviors in this model. Pretreatments with combinations of low doses of MS (0.05-0.5 microg) and D-APV (1 microg) were maximally effective in returning all spontaneous behavioral activities to baseline.


CONCLUSIONS
Spinal administration of combined doses of NMDA receptor antagonist, D-APV, and MS reversed three behavioral responses to induction of an acute pancreatitis model. These results suggest that in the clinical management of visceral pain, such as pancreatitis, restricted usage of glutamate antagonists might be useful as adjuvant potentiation at the onset of morphine therapy.
Lu
Ying
Y
Department of Anatomy and Neurosciences, The University of Texas Medical Branch, Galveston 77555-1043, USA.
Vera-Portocarrero
Louis P
LP
Westlund
Karin N
KN
D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy*; D010195:Pancreatitis / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine; D001920:Bradykinin