Stress-induced muscle and cutaneous hyperalgesia: Differential effect of milnacipran Heberto Suarez-Roca a, ⁎ , Luis Quintero a , Jose Luis Arcaya a , William Maixner b , Srinivas G. Rao c a Instituto de Investigaciones Clinicas, Section of Neuropharmacology, University of Zulia, Apartado 23, Maracaibo, 4001-A, Venezuela b The Center for Neurosensory Disorder, University of North Carolina at Chapel Hill, Rm 2111 Old Dental Bldg, CB#7455, Chapel Hill, NC 27599-7455, United States c Cypress Bioscience, Inc., 4350 Executive Dr., Suite 325, San Diego, CA 92121, United States Received 27 September 2005; received in revised form 8 March 2006; accepted 8 March 2006 Abstract We previously demonstrated that repeated swim stress produces long-term cutaneous hyperalgesia in rats. We have now determined the effect of stress upon muscle nociception and the anti-nociceptive efficacy of the norepinephrine–serotonin reuptake inhibitor, milnacipran (MIL) in this model. Rats were subjected to either 10–20 min daily sessions of forced swimming (FS) for 3 days, or sham swimming (SS) or control (CT). Maximal forelimb grip strength and hot plate response latencies were estimated before and after the conditioning to assess muscle and thermal nociception, respectively. MIL (1–30 mg/kg/i.p.) or vehicle was started 7 days before the conditioning protocol. There were significant reductions in maximal grip strength and hot plate latencies only in FS/vehicle rats. Subsequent carrageenan administration (2 mg/75 μl each triceps) diminished grip strength in all groups 24 h later, with grip strength lower in FS/vehicle and SS/vehicle rats than in CT/vehicle rats. Treatment with MIL before the stress prevented the reduction in grip strength in all groups but it was ineffective in preventing FS-induced reductions in hot plate response latencies. Thus, repeated stress produces muscle hyperalgesia that can be pharmacologically dissociated from cutaneous hyperalgesia, suggesting that different mechanisms may underlie these two phenomena. © 2006 Elsevier Inc. All rights reserved. Keywords: Stress; Cutaneous hyperalgesia; Muscle hyperalgesia; Antidepressants; Forced swimming 1. Introduction Acute exposure to stress is widely known to elicit cutaneous analgesia [1–3]. Yet, acute stress can induce brief enhancement of thermal or mechanical cutaneous nociception, assessed with reflex measurements, under some experimental conditions, such as, short exposures to horizontal oscillations [4], ether vapors [4], inescapable holding [5], novel environment [5], restraint/ vibration [6], and partial restraint [7]. Also, acute stress produces cutaneous hyperalgesia when evaluated with learned escape responses [8]. After repeated stress exposures, such as, cold environment (4 °C for 30 min every hour for one day) [9] and 1-h restraint a day for 40 days [10], rats display long-lasting mechanical and thermal cutaneous hyperalgesia, respectively. In agreement, we have previously demonstrated that repeated inescapable swim stress produces a delayed and long-term cutaneous hyperalgesia to both brief thermal and prolonged chemical stimuli in rats [11]. It is not known if this hyperalgesic state is associated with deeper structures such as muscle and viscera. Interestingly, repeated stress-induced hyperalgesia repro- duces many of the general clinical features associated with chronic muscle pain syndromes in humans including: 1) the presence of cutaneous hyperalgesia [12]; 2) a life relevant psychological stress associated with the onset and maintenance of the condition [13]; and 3) responsiveness to antidepressant Physiology & Behavior 88 (2006) 82 – 87 ⁎ Corresponding author. Instituto de Investigaciones Clínicas, Section of Pharmacology School of Medicine, University of Zulia. Calle 65 con Ave. 18A. Apartado Postal 23, Maracaibo 4001-A, Venezuela. Tel.: +58 416 660 6506; fax: +58 261 759 7247. E-mail address: hsuarezroca@yahoo.com (H. Suarez-Roca). 0031-9384/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2006.03.010