NK-1 receptors in the rostral ventromedial medulla contribute to hyperalgesia produced by intraplantar injection of capsaicin

Abstract

The rostral ventromedial medulla (RVM) is an area of the brainstem involved in the descending modulation of nociception at the level of the spinal cord. Although the RVM is involved in the inhibition or facilitation of nociception, the underlying mechanisms are not understood. Here we examined the role of the neuropeptide substance P and neurokinin-1 (NK-1) receptors located in the RVM on withdrawal responses evoked by mechanical and heat stimuli applied to the rat hindpaw under normal conditions and during hyperalgesia produced by capsaicin. The mechanical withdrawal threshold was obtained using von Frey monofilaments applied to the plantar surface of the hindpaw. Sensitivity to heat was determined by measuring the latency to withdrawal from radiant heat applied to the plantar surface. Mechanical and heat hyperalgesia were defined as a decrease in withdrawal response threshold or latency, respectively. Rats were prepared with a chronic cannula and either vehicle or the NK-1 receptor antagonists, L-733,060 or RP-67580, was injected into the RVM. Paw withdrawal responses were obtained before and after RVM injection, and then at 5, 30, and 60 min after an intraplantar injection of capsaicin (10 microg). Injection of the NK-1 antagonists at doses of 0.5 pmol or higher did not alter withdrawal responses to mechanical or heat stimuli under normal conditions but reduced the duration of nocifensive behavior and the mechanical and heat hyperalgesia produced by capsaicin. These findings suggest that the activation of NK-1 receptors in the RVM contributes to the hyperalgesia produced by capsaicin.

Substance P induces gastric mucosal protection at supraspinal level via increasing the level of endomorphin-2 in rats

“…dose of L-733,060 and GR 159897 in rats, however a wide dose range (from picomolar to micromolar: Pacharinsak et al, 2008;Rittner et al, 2007;Walsh et al, 1995) was used in the case of other routes of administration. The applied doses in the present study (1 nmol for L-733,060 and 0.5 nmol for GR 159897) were based partly on our preliminary results, partly on the estimated affinity of these ligands for the NK1 and NK2 receptors, respectively, derived from in vitro studies (Beresford et al, 1995;Seabrook et al, 1996).…”

Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury

“…Their responsiveness to excitatory glutamatergic inputs is not altered after inflammatory injury. In the absence of inflammatory injury, microinjection of NK1 receptor antagonists in the RVM does not alter either thermal or mechanical thresholds to noxious stimulation (Pacharinsak et al 2008) (M. Hamity, S. White, and D. L. Hammond, unpublished observations). Thus, it is unlikely that this class of neuron is involved in the modulation of persistent inflammatory nociception in the spinal cord dorsal horn (Kincaid et al 2006;Xu et al 2007; but see Miki et al 2002).…”

“…However, the responsiveness of these neurons to excitatory glutamatergic inputs is dramatically increased after inflammatory injury, an effect that is prevented by a low concentration of L-703,606. Microinjection of NK1 receptor antagonists in the RVM alleviates thermal hyperalgesia and mechanical allodynia produced by intradermal capsaicin (Pacharinsak et al 2008) or intraplantar injection of CFA in the hindpaw (Hamity et al 2008). Thus a subset of type 2 nonserotonergic neurons are likely to function as pain facilitatory neurons.…”

“…Spinally projecting RVM neurons have long been implicated in the inhibition and, more recently, in the facilitation of nociception (Hammond 1986;Porreca et al 2002;Urban and Gebhart 1999;Vanegas and Schaible 2004). Indeed RVM neurons can sustain thermal hyperalgesia or mechanical allodynia after peripheral injury (Burgess et al 2002;Pacharinsak et al 2008).…”

Glial Modulation of Pain: A Step Beyond: Figure 1.

“…Which substances mediate this process? While it is not determined, there are many options based on the following evidence: (1) glutamate; intra-RVM administration of a NMDA receptor antagonist (MK-801) reduces neuropathic pain; the activation of glial cells in the spinal cord during a neuropathic process is also blocked by intrathecal MK-801 (Wei and Pertovaara, 1999;Watkins and Maier, 2002); (2) cholecystokinin (CCK); CCK B receptor antagonist into RVM also reduced neuropathic pain (Kovelowski et al, 2000); (3) ATP; several ATP purinergic receptors are detected in RVM, and direct application of ATP in this area modulates the activity of a subclass of neurons (Selden et al, 2007); (4) substance P (SP); NK-1 receptor located in RVM contributes to hyperalgesia induced by capsaicin (Pacharinsak et al, 2008); SP is also implicated in peripheral nerve lesion-induced glial cell activation in the spinal cord (Watkins and Maier, 2002); and (5) fractalkine; CX3CR1 receptor is constitutively expressed in RVM, and fractalkine is a well known activator of microglia in the spinal cord during neuropathies (Watkins and Maier, 2002;Zhang et al, 2008). Wei et al (2008) found that activation of microglia and astrocytes had different time courses.…”