Elsevier

Neuroscience

Volume 52, Issue 4, February 1993, Pages 1039-1047
Neuroscience

CP-96,345, but not its stereoisomer, CP-96,344, blocks the nociceptive responses to intrathecally administered substance P and to noxious thermal and chemical stimuli in the rat

https://doi.org/10.1016/0306-4522(93)90550-YGet rights and content

Abstract

The effects of subcutaneous administration of the non-peptide NK-1 (substance P) receptor antagonist, CP-96,345, and its stereoisomer, CP-96,344, were tested in three nociceptive paradigms in the rat. In the first paradigm, tail flick responses were monitored before and after intrathecal administration of substance P (6.5 nmol) in rats pretreated subcutaneously with saline, CP-96,344 (5 mg/kg) or CP-96,345 (5 mg/kg). In the control groups, pretreated with saline (n = 6) or with CP-96,344 (n = 5), substance P reduced the tail flick reaction time at 1 min after administration to 38.3 ± 5.1 (mean ±S.E.M.) and 32.1 ± 7.7% of the mean baseline value, respectively. In contrast, in the group pretreated with CP-96,345 (n = 6) the reaction time following administration of substance P was 98.8 ± 3.3% of the baseline reaction time; this value was not significantly different from the baseline value of this group, indicating a block (P < 0.01) of the substance P-induced facilitation of the tail flick response.

In the second paradigm, rats were anesthetized with a mixture of chloral hydrate (120 mg/kg, i.p.) and sodium pentobarbital (20 mg/kg, i.p.), and the effects were determined on tail flick reaction time of a sustained noxious cutaneous stimulation, immersing the tip of the tail in hot water at 55°C. In the groups of rats pretreated with saline (n = 4) or with CP-96,344 (n = 7 ), this noxious stimulus produced a transient decrease in reaction time to 62–74% of the baseline value. However, in the group given CP-96,345 (n = 6), the reaction time was 97.4 ± 13.7% of the baseline reaction time, again indicating a block of the transient response and the involvement of NK-1 receptors.

In the third paradigm, nociceptive scores were determined after subcutaneous injection of 50 μl of 2.5% formalin into one hind paw. The first phase of the response to this noxious chemical stimulus was similar in rats pretreated with saline, with CP-96,344 and with CP-96,345. The second phase was also unaffected in rats pretreated with saline (n = 10), with 20 mg/kg of CP-96,344 (n = 8) or with 5 mg/kg of CP-96,345 (n = 9). However, in the groups given 10 (n = 8) or 20 (n = 6) mg/kg of CP-96,345, there was a significant reduction in this second phase (P < 0.05−0.01). indicating an involvement of NK-1 receptors in evoking this second phase.

The results indicate the efficacy of a systemically administered NK-1 receptor antagonist in blocking substance P-induced facilitation of a spinal nociceptive reflex and the stereospecificity of the actions of CP-96,345 in nociceptive tests. The data support the involvement of substance P or a related agent, acting via NK-1 receptors, in nociceptive responses to sustained noxious thermal and noxious chemical stimuli. NK-1 receptor antagonists may, therefore, be useful in the clinical treatment of pain originating from burns or lacerations of the skin or from inflamed tissue.

Reference (64)

  • GaumannD.M. et al.

    Intrathecal somatostatin, somatostatin analogs, substance P analog and dynorphin A cause comparable neurotoxicity in rats

    Neuroscience

    (1990)
  • HenryJ.L.

    Effects of substance P on functionally identified units in cat spinal cord

    Brain Res.

    (1976)
  • HenryJ.L. et al.

    Effects of substance P on nociceptive and non-nociceptive trigeminal brain stem neurons

    Pain

    (1980)
  • HökfeltT. et al.

    Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons

    Brain Res.

    (1975)
  • HollandL.N. et al.

    Changes of substance P-like immunoreactivity in the dorsal horn are associated with the ‘phasic’ behavioral response to a formalin stimulus

    Brain Res.

    (1990)
  • HunskaarS. et al.

    The formalin test in mice: dissociation between inflammatory and non-inflammatory pain

    Pain

    (1987)
  • IsabelG. et al.

    Design for an inexpensive unit for measuring tail flick latencies

    J. Pharmac. Meth.

    (1981)
  • KuraishiY. et al.

    Stimulus specificity of peripherally evoked substance P release from the rabbit dorsal horn in situ

    Neuroscience

    (1989)
  • McCarsonK.E. et al.

    Release of substance P into the superficial dorsal horn following nociceptive activation of the hindpaw of the rat

    Brain Res.

    (1991)
  • MurrayC.W. et al.

    Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model

    Pain

    (1991)
  • RadhakrishnanV. et al.

    Novel substance P antagonist, CP-96,345, blocks responses of spinal dorsal horn neurons to noxious cutaneous stimulation and to substance P

    Neurosci. Lett.

    (1991)
  • RochfordJ. et al.

    Lack of effect of adrenal denervation on analgesia elicited by continuous and intermittent cold water swim in the rat

    Brain Res.

    (1988)
  • SalterM.W. et al.

    Purine-induced depression of dorsal horn neurons in the cat spinal cord: enhancement by tachykinins

    Neuroscience

    (1987)
  • SalterM.W. et al.

    Tachykinins enhance the depression of spinal nociceptive neurons caused by cutaneously applied vibration in the cat

    Neuroscience

    (1988)
  • SalterM.W. et al.

    Responses of functionally identified neurones in the dorsal horn of the cat spinal cord to substance P, neurokinin A and physalaemin

    Neuroscience

    (1991)
  • SchmidtA.W. et al.

    The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels

    Eur. J. Pharmac.

    (1992)
  • ShibataM. et al.

    Modified formalin test: characteristic biphasic pain response

    Pain

    (1989)
  • TakahashiT. et al.

    Regional distribution of substance P in the spinal cord and nerve roots of the cat and the effect of dorsal root section

    Brain Res.

    (1975)
  • TheriaultE. et al.

    Capsaicin-evoked release of substance P from primary sensory neurons

    Brain Res.

    (1979)
  • YamamotoT. et al.

    Stereospecific effects of a nonpeptidic NK1 selective antagonist, CP-96,345: antinociception in the absence of motor dysfunction

    Life Sci.

    (1991)
  • YashpalK. et al.

    Quantitative autoradiographic distribution of multiple neurokinin binding sites in rat spinal cord

    Brain Res.

    (1990)
  • YashpalK. et al.

    Effects of dorsal rhizotomy on neurokinin receptor sub-types in the rat spinal cord: a quantitative autoradiographic study

    Brain Res.

    (1991)
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