Abstract
The analgesic effects of local administration of opioid agonists into peripheral tissues in alleviating pain have been well documented in both clinical and preclinical studies, although few studies have examined their effects in neuropathic pain. In this study, we investigated the anti-allodynic effects of peripherally acting delta opioid receptor (DOR) agonists in a rat model of neuropathic pain. Peripheral nerve injury (PNI) produced a time-dependent decrease in mechanical withdrawal thresholds that was attenuated by local administration into the hind paw of either morphine or the DOR agonist deltorphin II. Using Western blotting techniques, no change in DOR protein expression was detected in DRG ipsilateral to the site of injury compared to contralateral. However, an up-regulation of DOR protein was found in neuropathic DRG compared to sham, suggesting that there may be a bilateral increase in the expression of DOR following PNI. Results obtained from immunohistochemical studies confirmed up-regulation in small and large DRG neurons in neuropathic compared to sham animals. Additionally, there was an increase in DOR protein within the ipsilateral sciatic nerve of neuropathic animals compared to sham and contralateral neuropathic conditions indicating the occurrence of receptor trafficking to the site of injury. Taken together, our findings suggest that functional peripheral DORs are present in sensory neurons following PNI and validate the development of selective DOR agonists for alleviating neuropathic pain.
Highlights
In the peripheral nervous system, opioid receptors (OR) are synthesized in the cell bodies of primary afferent neurons located in dorsal root ganglia (DRG) and targeted to terminals present in the superficial dorsal spinal cord and peripheral sensory nerve endings (Fields et al, 1980; Hassan et al, 1993; Coggeshall et al, 1997)
Peripheral nerve injury to the sciatic nerve resulted in a significant decrease in mechanical withdrawal thresholds on days 7, 14 and up to day 25 following surgery compared to baseline pre-surgical values, which represents hypersensitivity to non-noxious tactile stimulation, and is interpreted as tactile allodynia
Deltorphin II maintained its anti-allodynic effects at later time points following nerve injury
Summary
In the peripheral nervous system, opioid receptors (OR) are synthesized in the cell bodies of primary afferent neurons located in dorsal root ganglia (DRG) and targeted to terminals present in the superficial dorsal spinal cord and peripheral sensory nerve endings (Fields et al, 1980; Hassan et al, 1993; Coggeshall et al, 1997). While most studies have evaluated the effects of OR agonists following systemic administration, the analgesic effects of peripherally restricted opioid agonists has been more lim-. Local peripheral administration of mu-, delta-, and kappa-OR agonists have been shown to elicit dose-dependent, stereo-selective anti-hyperalgesic effects in models of inflammatory pain (Stein et al, 1989). Mu OR (MOR) agonists have been shown to reverse bradykinin- and prostaglandin E2-induced hyperalgesia following their injection into the experimental paw (Levine and Taiwo, 1989; Taiwo and Levine, 1991). Clinical studies examining peripheral opioid analgesia have shown that intra-articular administration of morphine exerts potent and long-lasting postoperative analgesia following knee surgery (Stein et al, 1991; Stein et al, 1999). Locally administered morphine has been shown to elicit effective
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