Stress-induced muscle and cutaneous hyperalgesia: differential effect of milnacipran.

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 microl 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.

Role of mu-opioid and NMDA receptors in the development and maintenance of repeated swim stress-induced thermal hyperalgesia.

Repeated exposure to swimming stress induces a long-lasting hyperalgesia in the rat by mechanisms to be elucidated. Since opioid and glutamate neurotransmitter systems modulate pain, we now evaluated the effect of pharmacological blockade of opioid and glutamate receptors subtypes on forced swimming stress-induced hyperalgesia. Male rats were daily subjected to 10-20 min of forced or sham swimming for 3 days and thermal nociception was estimated twice, before each behavioral conditioning and 24 h after the last, using hot plate test. Selective opioid and NMDA receptor antagonists were administered i.p. either before each conditioning session or before the second nociception assessment. Unlike sham swimming rats, forced swimming rats showed significant reductions in hot plate response latencies (hyperalgesia) after the last swimming session, as compared to pre-stress values. Rats treated with the opioid receptor antagonists naloxone (0.1 mg/kg, non-subtype-selective) and naloxonazine (5 mg/kg, mu(1)-subtype-selective), before each forced swimming, did not become hyperalgesic, whereas those treated before the second post-stress assessment of nociception developed hyperalgesia. Naltrindole (0.5 mg/kg, delta-subtype-selective) and nor-binaltorphimine (0.5mg/kg, kappa-subtype-selective) were inactive in both administration schedules. The efficacy of morphine (3-7.5 mg/kg) to produce analgesia in forced swimming rats was lower than in sham swimming rats. Rats treated with the NMDA antagonist ketamine (5 mg/kg) before the forced swimming or the second post-stress assessment of nociception did not have hyperalgesia. Thus, swim stress-induced hyperalgesia might be initiated by the repeated stimulation of mu-opioid and NMDA receptors but maintained only by the activity of NMDA receptors.

Repeated swim stress increases pain-induced expression of c-Fos in the rat lumbar cord.

We have previously demonstrated that repeated swim stress produces a long-lasting cutaneous hyperalgesia in rats. We have now looked at c-Fos expression in the spinal lumbar cord of male Sprague-Dawley rats subjected to 10-20 min daily sessions of forced swimming for 3 consecutive days. Control rats were subjected to sham swimming or were completely naive. Forty-eight hours later, nociception was assessed by recording for 90 min the nociceptive behavior evoked the injection of 1% formalin in the hind paw. Thirty min later, the rats' spinal cords were removed for c-Fos immunocytochemistry. Total pain scores were 45% higher in swim stressed rats compared to control animals due an increased nociceptive behavior during last 70 min of the recording period. In addition, the number of c-Fos-immunoreactive nuclei was 40% higher in the lumbar ipsilateral dorsal horn (L4-L5) of swim stressed rats than in controls, being the highest relative increase, relative to the control groups, observed in laminae III-IV, followed by laminae V-VI, with the smallest difference in laminae I-II. c-Fos expression in the contralateral dorsal horn was higher in swim stressed rats than in sham and nai;ve rats. In the absence of a nociceptive stimulus, a low level of c-Fos expression was observed mainly in laminae I, II, V, and VI, being higher in swim stressed rats than in sham rats. These findings suggest that repeated inescapable and uncontrollable stress could induce a sensitization and activation of sensory neurons at the spinal level.