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13048.Full.Pdf 13048 • The Journal of Neuroscience, December 13, 2006 • 26(50):13048–13053 Behavioral/Systems/Cognitive Activation of Opioid Receptor Like-1 Receptor in the Spinal Cord Produces Sex-Specific Antinociception in the Rat: Estrogen Attenuates Antinociception in the Female, whereas Testosterone Is Required for the Expression of Antinociception in the Male Jomo Claiborne, Subodh Nag, and Sukhbir S. Mokha Division of Neurobiology and Neurotoxicology, Department of Biomedical Sciences, Meharry Medical College, Nashville, Tennessee 37208 Sex-related differences in the perception and modulation of pain have been reported. The present study is the first to investigate systematically whether activation of opioid receptor-like 1 receptor (ORL1 ) by orphanin FQ (OFQ) produces sex-specific modulation of spinal nociception and whether estrogen or testosterone contributes to these differences using the rat as an experimental animal. Two behavioral models, the NMDA and heat-induced nociceptive tests, were used to examine sex-specific modulation of spinal nociception. Intrathecal microinjection of OFQ in male, ovariectomized (OVX), and diestrous rats produced a significant antinociceptive effect on both tests. However, OFQ failed to produce antinociception in proestrous rats, the phase of the estrous cycle with the highest levels of circulating estradiol, and produced a dose-dependent effect in OVX females treated with 1 ng to 100 ␮g of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe 1,Arg 14,Lys 15]N/ OFQ(1–13)-NH2 ), an ORL1 receptor-selective antagonist. Interestingly, OFQ was ineffective in gonadectomized (GDX) males, whereas testosterone replacement restored the antinociceptive effect of OFQ in GDX males. We conclude that OFQ produces sex-specific modu- lation of spinal nociception; estrogen attenuates antinociception in the female in parallel with normal cycling of estrogen levels, and testosterone is required for the expression of antinociception in the male; thus, the sensitivity of the male to the antinociceptive effects of OFQ is not simply attributable to the intrinsically low estrogen levels in these animals. Key words: orphanin FQ; opioid receptor like-1 receptor; ORL1 ; sex differences; pain; tail flick; analgesia Introduction opioid receptor-like-1 receptor (ORL1) (Bunzow et al., 1994, Sex-related differences have been reported in the perception and Mollereau et al., 1994). Although ORL1 shares substantial homol- modulation of pain. Women exhibit enhanced sensitivity to ex- ogy with the classical opioid receptors (␮, ␦, and ␬) (Chen et al., perimental pain (for review, see Fillingim and Maixner, 1995) 1994; Mollereau et al., 1994), OFQ displays low affinity for the and experience a greater prevalence of pain disorders (Fillingim classical opioid receptors, and, reciprocally, agonists of classical and Maixner, 1995) (for review, see Berkley, 1997). Sex-related opioid receptors display low affinity for the ORL1 receptor differences in pain modulation by activation of G-protein- (Mollereau et al., 1994; Mogil and Pasternak, 2001). ␮ ␬ ␣ coupled receptors such as opioid ( and ) and 2 noradrenergic The ORL1 receptor is expressed in the superficial laminas of receptors have been demonstrated in human and animal studies the spinal dorsal horn, an area involved in receiving and process- (Gear et al., 1996; Mitrovic et al., 2003; Mogil et al., 2003; Fill- ing nociceptive information (Bunzow et al., 1994; Mollereau et ingim and Gear, 2004; Nag and Mokha, 2006; Peckham and al., 1994, 1996) (for review, see Mogil and Pasternak, 2001). OFQ Traynor, 2006). has been reported to produce pronociceptive or antinociceptive The present study focuses on orphanin FQ (OFQ) (Meunier et effects, depending on the route of administration (Meunier et al., al., 1995; Reinscheid et al., 1995), an endogenous ligand for the 1995; Reinscheid et al., 1995; Erb et al., 1997; Calo´ et al., 2000). Intracerebroventricular administration of OFQ has been re- ported to produce (1) hyperalgesia (Meunier et al., 1995; Rein- Received June 14, 2006; revised Nov. 9, 2006; accepted Nov. 9, 2006. This study was supported by National Institutes of Health Grants GM008037, U54 NS041071, RR03032, and scheid et al., 1995; Wang et al., 1999), (2) hyperalgesia followed MH65782. We thank Dr. Lee E. Limbird for her comments on this manuscript. by analgesia (Rossi et al., 1996), and (3) reversal of opioid- Correspondence should be addressed to Dr. Sukhbir S. Mokha, Division of Neurobiology and Neurotoxicology, induced analgesia (Grisel et al., 1996; Mogil et al., 1996; Hein- Department of Biomedical Sciences, Meharry Medical College, 1005 D. B. Todd Boulevard, Nashville, TN 37208. richer et al., 1997; Bertorelli et al., 1999). However, a consensus E-mail: [email protected]. DOI:10.1523/JNEUROSCI.4783-06.2006 has emerged that intrathecal application of OFQ into the spinal Copyright © 2006 Society for Neuroscience 0270-6474/06/2613048-06$15.00/0 cord primarily produces analgesia (Xu et al., 1996; King et al., • Claiborne et al. ORL1 and Sex Differences in Pain J. Neurosci., December 13, 2006 • 26(50):13048–13053 • 13049 1997; Yamamoto and Nozaki-Taguchi, 1997; Yamamoto et al., levels in normally cycling females at proestrous (ProE) and diestrous 1997, 1999; Hao and Ogawa, 1998; Hao et al., 1998; Wang et al., stages (63.28 Ϯ 4.32 and 32.59 Ϯ 3.09 pg/ml, respectively; n ϭ 6 per 1999; Yamamoto and Sakashita, 1999) (for review, see Mogil and group). The estrogen levels were found to be within physiological range 48 h after estradiol injection, the time point when all nociceptive testing Pasternak, 2001; Meunier, 2003). Whether activation of ORL1 in the spinal cord produces sex-specific modulation of nociception re- is conducted. Furthermore, estradiol levels at this time point after the 100 ␮g dose of estrogen were similar to that reported previously in normally mains unknown. cycling females at the proestrous stage (Butcher et al., 1974). The present investigation was designed to examine whether OFQ and UFP-101. Three doses of OFQ (2.5, 5, and 10 nmol/10 ␮l, i.t.) OFQ produces sex-specific modulation of spinal nociception in were administered in separate groups of male and OVX animals, and the the rat using two complementary behavioral measures of noci- effects were examined on the thermal stimulus-induced tail-flick reflex. 1 14 15 ␮ ception: NMDA-induced nociceptive scratching, biting, and lick- UFP-101 ([Nphe ,Arg ,Lys ]N/OFQ(1–13)-NH2) (10 nmol/5 l, ing behavior assay (Aanonsen and Wilcox, 1987) and the noxious i.t.), an ORL1 antagonist, was administered 4 min before administration heat-induced tail-flick reflex (D’Amour and Smith, 1941). The of OFQ (5 nmol/10 ␮l, i.t.) in male and OVX female rats. role of the gonadal steroids estrogen and testosterone in modu- All chemicals were obtained from Sigma (St. Louis, MO) except for lating this nociception also was determined. UFP-101 (Tocris Cookson, Ballwin, MO). NMDA-induced nociception. NMDA (4 nmol/10 ␮l) (Aanonsen and Wilcox, 1987) was injected into the lumbar spinal cord through the Materials and Methods implanted cannulas followed by 10 ␮l of sterile saline. NMDA induced Animals. The experimental groups consisted of male, female gonadecto- intense scratching/biting/licking behavior that lasted up to 4 min. The mized (GDX) male, and ovariectomized (OVX) female Sprague Dawley number of scratches/bites aimed at the hindlimb area, the latency to rats (Harlan Sprague Dawley, Indianapolis, IN). The animals were scratching behavior, and the duration of the scratching behavior were housed in the Meharry Medical College animal care facility certified by manually recorded. Higher doses of NMDA resulted in clearly aversive the American Association for the Accreditation of Laboratory Animal behavior (escape attempts and vocalizations) in pilot experiments and ␮ Care under a 12 h light/dark cycle (lights on at 7:00 AM and lights off at therefore were excluded. OFQ (10 nmol/10 l, i.t.) was administered 10 ␮ 7:00 PM). Food and water were available ad libitum. The experimental min before administration of NMDA (4 nmol/10 l). protocols were approved by the Institutional Animal Care and Use Com- Tail-flick test. Tail-flick latency (TFL) (D’Amour and Smith, 1941) was mittee of Meharry Medical College and abided by the established guide- measured automatically by a tail-flick analgesia meter (model 33T; IITC lines of the National Research Council Guide for the Care and Use of Life Science, Woodland Hills, CA). Animals were loosely restrained in a Laboratory Animals. Plexiglas cylinder with the dorsal surface of the tail exposed to a radiant Estrous cycle stages were determined by the standard vaginal smear heat source mounted 8 cm above the cylinder. A beam of focused radiant test. Female rats were operated on in the diestrous (DiE) phase and heat was applied 3–7 cm from the tip of the rat’s tail; the radiant heat was underwent nociceptive testing after having established two regular ovar- applied at three separate spots to prevent sensitization as a result of ian cycles. heating the same spot in succession. An automatic cutoff latency of 15 s Implantation of intrathecal cannulas. Cannulas were implanted in an- was set to prevent tissue damage. Before the tail-flick test, the animals imals under ketamine and xylazine anesthesia (72 and 4 mg/kg, i.p., were allowed to acclimate to the restraint cylinder for 15 min. The heat respectively). The head of the rat was secured in a stereotaxic frame intensity was adjusted to produce a baseline TFL of between 3 and 5 s. (David Kopf Instruments, Tujunga, CA), and an incision was made Three baseline readings were taken at 2 min intervals before intrathecal above the atlantooccipital membrane, which was cleared to expose the injection of OFQ. TFLs were determined every 2 min for 20 min after dura. A stretched polyethylene-10 cannula (Intramedic; dead volume, 10 injection of OFQ.
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