Elsevier

Brain Research

Volume 1268, 1 May 2009, Pages 58-67
Brain Research

Research Report
Antagonism of TRPV1 receptors indirectly modulates activity of thermoregulatory neurons in the medial preoptic area of rats

https://doi.org/10.1016/j.brainres.2009.02.018Get rights and content

Abstract

In order to enhance understanding of TRPV1 contributions to thermoregulation, we measured the effects of a TRPV1 receptor antagonist, A-889425, on thermoregulatory neurons in the medial preoptic area of the hypothalamus (mPOA) of rats while simultaneously monitoring rectal temperature (Tr). Administration of A-889425 (4Ā Ī¼mol/kg, i.v.) significantly increased Tr by 0.42Ā Ā±Ā 0.02Ā Ā°C in anesthetized rats. Warm-sensitive (WS) neurons in the mPOA increase firing in response to body warming, and when active stimulate heat loss and inhibit heat production. WS neurons were initially inhibited by A-889425. Subsequently, WS neuronal activity diverged, differentiating WS neurons into two subgroups. One group of WS neurons continued to be inhibited during the recording period while another group of ā€œbiphasicā€ WS neurons increased firing as Tr increased. Cold-sensitive (CS) neurons fire at a higher rate during cooling of the body, and when active, may contribute to heat production. Injection of A-889425 affected CS neurons in a manner opposite to the biphasic WS neurons; activity was initially increased followed by a later decrease. Direct administration of A-889425 into the mPOA (10 and 30Ā nmol) or spinal cord (30Ā nmol) did not affect Tr. Disruption of abdominal TRPV1 receptor function by injection of the TRPV1 receptor agonist, resiniferatoxin (20Ā Ī¼g/kg, i.p.), 9ā€“15Ā days prior to experiments, blocked the effects of systemically injected A-889425 on Tr and mPOA neuronal activity. These data demonstrate that antagonist block of abdominal TRPV1 receptors indirectly modulates activity of thermoregulatory neurons in the mPOA in a manner that is consistent with producing an acute rise in body temperature.

Introduction

In the past few years there has been a surge in research efforts to identify and develop selective TRPV1 receptor antagonists since it is now well appreciated that blocking TRPV1 receptors is an effective means to reduce normal and pathological nociception in rats. Administration of TRPV1 receptor antagonists decreases the transmission of nociceptive signals to the spinal cord following high-intensity peripheral stimulation in uninjured animals (Davis et al., 2000, Kelly and Chapman, 2002, McGaraughty et al., 2006). More importantly, TRPV1 receptor antagonists also attenuate hyperalgesia and allodynia in several models of pathological pain (Cui et al., 2006, Culshaw et al., 2006, Gavva et al., 2005, Ghilardi et al., 2005, Honore et al., 2005, Varga et al., 2005, Wang et al., 2007). The effects of the antagonists are mediated at peripheral, spinal (Caterina et al., 1997, Guo et al., 1999, Kelly and Chapman, 2002, Tominaga et al., 1998, Valtschanoff et al., 2001), as well as supraspinal TRPV1 receptors (for a review see McGaraughty and Bitner, 2007).

In addition to actions on the nociceptive system, several TRPV1 receptor antagonists have been reported to also affect thermoregulation by transiently raising core body temperature following systemic administration in both animals and humans (Gavva et al., 2007a, Gavva et al., 2007b, Gavva, et al., 2008, Steiner et al., 2007, Swanson et al., 2005). This outcome is consistent with the well-known hypothermic effects of TRPV1 receptor agonists (Hajos et al., 1987, Jancso-Gabor et al., 1970a, Jancso-Gabor et al., 1970b, Miller et al., 1982). Additionally, ablation of the TRPV1 gene eliminates both agonist-induced hypothermia (Caterina et al., 2000) and antagonist-induced hyperthermia (Steiner et al., 2007). Both central and peripheral TRPV1 receptors may contribute to the modulation of thermoregulation (Caterina, 2007). Direct injection of TRPV1 receptor agonists into central sites, such as the medial preoptic area (mPOA) of the hypothalamus, results in hypothermia (Dib, 1987, Hajos et al., 1987, Jancso-Gabor et al., 1970b). The mPOA is an important center in the integrative control of body temperature (Boulant, 2000, Romanovsky, 2007), and TRPV1 receptors are expressed in this region (Acs and Palkovits, 1996, Mezey et al., 2000). However, Steiner et al. (2007) demonstrated that antagonist blockade of abdominal, but not central, TRPV1 receptors leads to a rise in rat body temperature.

Three different classes of thermoregulatory neurons have been identified in the mPOA (Boulant, 2000). Warm-sensitive (WS) neurons increase firing in response to local or peripheral warming, and when active, stimulate heat loss and inhibit heat production. Cold-sensitive (CS) neurons fire at a higher rate following local or peripheral cooling. When active, CS neurons may stimulate heat production. However, the thermoregulatory role of the relatively few CS neurons is still being investigated and may be secondary to the activity of WS neurons (Chen et al., 1998, Kanosue et al., 1994a, Kanosue et al., 1994b, Zhang et al., 1995). Non-responsive (NR) neurons do not respond to temperature changes, and their role in thermoregulation, if any, is unknown. Systemic or direct injection of the TRPV1 receptor agonist, capsaicin, into the mPOA region excites WS neurons and inhibits CS neurons (Hori et al., 1988). The purpose of the current study is to determine, in vivo, the systemic effects of a selective TRPV1 receptor antagonist, A-889425 (Fig. 1) (Brown et al., 2008, McGaraughty et al., 2008), on the firing of mPOA thermoregulatory neurons and to relate the resultant change in neuronal activity to changes in body temperature. Additionally, the contribution of mPOA, spinal, and abdominal TRPV1 receptors to the systemic effects of A-889425 was also investigated.

Section snippets

In vivo electrophysiology and temperature measurement in anesthetized rats

Discharge activity was recorded from 34 mPOA neurons of anesthetized naive rats, and each was characterized by responses to cool and warm stimulation (Fig. 2). Spontaneous firing prior to drug administration for WS and CS neurons was 2.48Ā Ā±Ā 0.67 and 1.36Ā Ā±Ā 0.53 spikes/s, respectively. Baseline spontaneous firing for NR neurons was 4.85Ā Ā±Ā 1.31 spikes/s. Since vehicle did not alter the firing of any class of mPOA neuron, this data was combined (nĀ =Ā 9) for later comparison. Tr was continuously monitored

Discussion

Systemic administration of the selective TRPV1 receptor antagonist, A-889425, has been shown to reduce behavioral and spinal neuronal responses to noxious mechanical stimulation in inflamed rats (McGaraughty et al., 2008). In the current study, comparable doses of A-889425 raised rectal temperature in naive rats. This latter result is consistent with previous studies demonstrating a similar effect of other TRPV1 receptor antagonists on thermoregulation (Gavva et al., 2007a, Gavva et al., 2007b,

Experimental procedures

All animal handling and experimental protocols were approved by Abbott's Institutional Animal Care and Use Committee (IACUC), and were conducted in accordance with the ethical principles for pain-related animal research of the American Pain Society. Male Spragueā€“Dawley rats (Charles River, MA, 300ā€“425Ā g) were used for all experiments and were housed in a temperature controlled room with a 12/12-h day/night cycle. Food and water were available ad libitum.

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