Escalating morphine dosage fails to elicit conditioned analgesia in a preclinical chronic neuropathic pain model.

Many people with chronic pain escalate their opioid dosage to counteract tolerance effects. A treatment regimen consisting of placebos admixed with opioids has been suggested as a possible therapeutic option that could reduce the harm of long-term opioid use. However, the analgesic efficacy of such a regimen requires further investigation before widespread adoption. We have recently reported that a 4-day pharmacological conditioning procedure, which paired morphine (6 mg/kg) with contextual cues, elicited placebo analgesia in subpopulations of male (35%) and female (25%) rats with sciatic nerve chronic constriction injury (CCI). Here, we investigated how an escalating morphine dosage during conditioning affects the incidence and strength of placebo analgesia. Forty-four male, Sprague-Dawley rats received CCI. Thirty-eight (86%) rats developed strong cold allodynia by day 6 post-surgery, as measured by hind paw withdrawal (HPW) behaviour on a 5°C cold plate (120 s). In this experiment, pharmacological conditioning consisted of an escalating morphine dose over 4 days (8/9/10/12 mg/kg). This dosing regimen produced strong reductions in HPW behaviour and counteracted the effects of morphine tolerance during conditioning. However, none of the rats given the placebo treatment (n = 12) demonstrated reductions in HPW behaviour when morphine was substituted for saline (i.e. placebo analgesia), but instead showed a strong behavioural response (rearing). These results demonstrate that a high, escalating dose of morphine failed to produce conditioned placebo analgesia in rats with CCI. It is possible that admixing placebos with opioids may be similarly ineffective in chronic pain patients when the opioids regimen is high or escalating.

Peripheral nerve injury attenuates stress-induced Fos-family expression in the Locus Coeruleus of male Sprague-Dawley rats.

The ability to cope with acute stressors is impaired in people with chronic neuropathic injuries. The regulation of stress coping responses depends critically on several parallel interconnected neural circuits, one of which originates in the Locus Coeruleus. In rats, chronic constriction injury (CCI) and acute stress each modulate noradrenergic activity of the Locus Coeruleus (LC) although with different temporal patterns. This study investigated the effects of CCI on the neuronal activity of the LC to acute restraint stress using the immunohistochemical detection of Fos-family protein expression. Male Sprague-Dawley rats underwent CCI surgery and 11 days later were restrained for 15 min. The number and location of single-labelled neurons (c-Fos, FosB/ΔFosB and tyrosine hydroxylase (TH) immunoreactive) neurons and double labelled neurons (c-Fos, or FosB/ΔFosB with TH) were quantified for the LC and surrounding regions. Comparisons were made with rats that underwent sham surgery or anaesthesia (20 min). Restraint triggered a struggling response in all rats. CCI attenuated restraint-induced Fos expression in LC neurons. A significant proportion (30-50%) of these LC Fos positive neurons did not contain TH. These data suggest that nerve injury might impair the ordinary cellular response of the LC to an acute stress. The association of stress-related disorders in people with neuropathic injuries suggests that the observations made in this study may reflect a part of the mechanism underlying these clinical comorbidities.