Spinal or systemic TY005, a peptidic opioid agonist/neurokinin 1 antagonist, attenuates pain with reduced tolerance.
OBJECTIVE
The use of opioids in treating pain is limited due to significant side effects including somnolence, constipation, analgesic tolerance, addiction and respiratory depression. Pre-clinical studies have shown that neurokinin 1 (NK(1) ) receptor antagonists block opioid-induced antinociceptive tolerance and may inhibit opioid-induced rewarding behaviours. Here, we have characterized a bifunctional peptide with both opioid agonist and NK(1) antagonist pharmacophores in a rodent model of neuropathic pain.


METHODS
Rats were evaluated for behavioural responses to both tactile and thermal stimuli in either an uninjured, sham- or nerve-injured state. TY005 (Tyr-DAla-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bn(CF(3) )(2) ) was delivered spinally or systemically to assess the antinociceptive effects after acute exposure. Motor skills were evaluated using the rotarod test to determine potential sedative effects. Spinal TY005 was given chronically to sham- or nerve-injured animals to determine the development of tolerance.


RESULTS
Bolus injections of TY005 produced dose-dependent antinociception in non-injured animals and alleviated nerve injury-induced thermal and tactile hypersensitivities (i.e. antihyperalgesia) more effectively than morphine. Sedative effects were not evident from the rotarod test at doses that were antihyperalgesic, nor at doses threefold higher. Repeated administration of TY005 did not lead to the development of antihyperalgesic tolerance or alter sensory thresholds.


CONCLUSIONS
Collectively, the data suggest that opioid agonist/NK(1) antagonist bifunctional peptides represent a promising novel approach to the management of chronic pain without the development of tolerance, reducing the need for escalation of doses and unwanted side effects associated with opiates alone.
Largent-Milnes
T M
TM
Department of Pharmacology, College of Medicine and Department of Chemistry, University of Arizona, Tucson, AZ 85724, USA.
Yamamoto
T
T
Nair
P
P
Moulton
J W
JW
Hruby
V J
VJ
Lai
J
J
Porreca
F
F
Vanderah
T W
TW
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists
D000701:Analgesics, Opioid; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; C521964:tyrosyl-alanyl-glycyl-phenylalanyl-methionyl-prolyl-leucyl-tryptophyl-O-3,5-benzyl(CF3)2