Nerve injury-induced mechanical but not thermal hyperalgesia is attenuated in neurokinin-1 receptor knockout mice.
Mice lacking the gene encoding for substance P and neurokinin A, or the NK-1 receptor, exhibit alterations in behavior to various acute nociceptive stimuli. However, behavioral responses of NK-1 mutant animals have not been well characterized in models of chronic pain. We studied the behavioral responses of NK-1 knockout and wild-type control mice to thermal and mechanical stimuli before and after inducing chronic neuropathic pain by unilateral ligation of the L5 spinal nerve. Mechanical hyperalgesia was evaluated by determining the frequency of withdrawal to von Frey monofilaments applied to the hind paws. Nerve injury-induced hyperalgesia to thermal stimuli was examined by determining responses to radiant heat and cooling stimuli. The contribution of the sympathetic nervous system to mechanical hyperalgesia was evaluated by administering 3 mg/kg phentolamine, an alpha-adrenergic antagonist, subcutaneously. Following spinal nerve injury, withdrawal frequencies to mechanical stimulation increased in wild-type mice within 1 day and persisted during the 9-week observation period, whereas in the knockout mice, withdrawal frequencies did not increase significantly. In contrast, withdrawal latencies to radiant heat decreased up to 2 weeks after nerve injury in both the NK-1 and the wild-type mice. Similarly, the increase in withdrawal frequency to the cooling stimuli following the nerve injury was not different in the NK-1 knockout and wild-type mice. Mechanical hyperalgesia in the wild-type mice was not reversed by systemic administration of phentolamine, suggesting that the pain is not sympathetically maintained. The results indicate that NK-1 receptors contribute to the development of mechanical, but not thermal, hyperalgesia in neuropathic pain.
Mansikka
H
H
Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Sheth
R N
RN
DeVries
C
C
Lee
H
H
Winchurch
R
R
Raja
S N
SN
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003080:Cold Temperature; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009437:Neuralgia / Q000503:physiopathology*; D010646:Phentolamine / Q000494:pharmacology; D010812:Physical Stimulation; D011597:Psychomotor Performance; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013127:Spinal Nerves / Q000293:injuries* / Q000503:physiopathology* / Q000601:surgery; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D014950:Wounds, Penetrating / Q000503:physiopathology*
D018040:Receptors, Neurokinin-1; D010646:Phentolamine